Two-directional desymmetrization by double 1,4-addition of silicon and boron nucleophiles

Article abstract of DOI:10.1021/ol300832f

The two-directional desymmetrization of prochiral precursors with α,β-unsaturated branches by catalyst-controlled 1,4-addition of silicon and likewise boron nucleophiles allows for a general enantioselective access to syn,anti-triols with 1,n + 1,2n + 1 (

Full text of DOI:10.1021/ol300832f

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2406–2409
Two-Directional Desymmetrization by
Double 1,4-Addition of Silicon and Boron
Nucleophiles
Eduard Hartmann and Martin Oestreich*
€
Institut fu€r Chemie, Technische Universitat Berlin, Strasse des 17. Juni 115, 10623
Berlin, Germany
martin.oestreich@tu-berlin.de
Received April 2, 2012
ABSTRACT
The two-directional desymmetrization of prochiral precursors with R,β-unsaturated branches by catalyst-controlled 1,4-addition of silicon and
likewise boron nucleophiles allows for a general enantioselective access to syn,anti-triols with 1,n þ 1,2n þ 1 (n = 2 and 3) substitution patterns.
The utility is demonstrated in the synthesis of the C17ꢀC25 fragment of dermostatin A.
Two-directional desymmetrization of achiral precursors
with a prochiral atom poses a remarkable stereochemical
situation.1 The twist in these enantioselective functionali-
zations2,3 is that, when performed double, diastereofacial
selectivity at the functional group of either enantiotopic
branch sets the absolute configuration at the newly formed
stereogenic center in the initial step. Its relative configura-
tion to the former prochiral center is, in turn, irrelevant
because, if the final step proceeds with the same diaster-
eofacial selectivity at the remaining branch of the now
chiral intermediate, that center becomes chirotopic. The
net stereochemical result of such a two-step process is the
transformation of a prochiral molecule into a pseudo-C2-
symmetric compound with a chirotopic atom flanked by
the new stereocenters; all stereochemical options are sche-
matically illustrated in the Supporting Information. Excep-
tional levels of enantio- and diastereoselectivity are foresee-
able when the asymmetric method is highly enantioselective
and exerts excellent catalyst control in both steps.4
Our laboratory developed a Rh(I)-catalyzed 1,4-addi-
tion of silicon nucleophiles to acylic R,β-unsaturated
carboxyl compounds with very high enantiocontrol
(>99% ee).5ꢀ7 The use of this methodology in iterative
(1) For reviews of two-directional synthesis, see: (a) Schreiber, S. L.
Chem. Scr. 1987, 27, 563–566. (b) Poss, C. R.; Schreiber, S. L. Acc.
Chem. Res. 1994, 27, 9–17. (c) Magnuson, S. R. Tetrahedron 1995, 51,
2167–2213.
(2) For selected examples of reagent-controlled asymmetric two-
directional syntheses with prochiral or meso precursors, see: (a) Wang,
Z.; Deschenes, D. J. Am. Chem. Soc. 1992, 114, 1090–1091. (b) Mitton-Fry,
M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem., Int. Ed. 2007, 46,
1066–1070. (c) Zhang, Y.; Arpin, C. C.; Cullen, A. J.; Mitton-Fry, M. J.;
Sammakia, T. J. Org. Chem. 2011, 76, 7641–7653.
(3) For selected examples of catalyst-controlled asymmetric two-
directional syntheses with prochiral or meso precursors, see: (a) Lucas,
B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915–3918. (b) Keller, V. A.; Kim,
I.; Burke, S. D. Org. Lett. 2005, 7, 737–740. (c) Wysocki, L. M.; Dodge,
M. W.; Voight, E. A.; Burke, S. D. Org. Lett. 2006, 8, 5637–5640. (d) Lu,
Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J. Angew. Chem.,
Int. Ed. 2009, 48, 5018–5021. (e) Han, S. B.; Hassan, A.; Kim, I. S.;
Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559–15561. (f) Gao, X.;
Han, H.; Krische, M. J. J. Am. Chem. Soc. 2011, 133, 12795–12800.
(4) Kinetic resolution effects might also be considered when asym-
metric induction of the used method is not high. For a scholarly example
producing a highly enantiomerically enriched monofunctionalized car-
binol, see: Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem.
Soc. 1987, 109, 1525–1529.
(5) For a comprehensive overview of asymmetric conjugate addition
reactions of silicon and boron nucleophiles, see: Hartmann, E.; Vyas,
D. J.; Oestreich, M. Chem. Commun. 2011, 47, 7917–7932.
(6) (a) Walter, C.; Oestreich, M. Angew. Chem., Int. Ed. 2008, 47,
€
3818–3820. (b) Walter, C.; Frohlich, R.; Oestreich, M. Tetrahedron
2009, 65, 5513–5520.
(7) For the recently developed Cu(I)-catalyzed asymmetric conjugate
silyl transfer, see: (a) Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010,
132, 2898–2900. (b) Harb, H. Y.; Collins, K. D.; Garcia Altur, J. V.;
Bowker, S.; Campbell, L.; Procter, D. J. Org. Lett. 2010, 12, 5446–5449.
ꢀ
(c) Ibrahem, I.; Santoro, S.; Himo, F.; Cordova, A. Adv. Synth. Catal.
2011, 353, 245–252.
r
10.1021/ol300832f
Published on Web 04/16/2012
2012 American Chemical Society

synthesis had already demonstrated its potential to override
substrate control for chiral δ-substituted R,β-unsaturated
acceptors.8 Application of that catalyst-controlled conju-
gate silyl transfer to two-directional desymmetrization of
carbinols with R,β-unsaturated substituentswould provide
a stereocontrolled one-pot access to triol surrogates with 1,
n þ 1,2n þ 1 (n = 2 and 3) substitution patterns (Ifsyn-II
and/or anti-IIfsyn,anti-III, Scheme 1, upper). Subsequent
oxidative degradation of the CꢀSi bonds9 and deprotec-
tionwouldthenaffordthetargetedtriols(IVtV, Scheme1,
middle). An alternative indirect approach to the long-
standing problem of asymmetric hydration of R,β-unsatu-
rated acceptors5 is the conjugate addition of a boron
nucleophile (Scheme 1, upper),10ꢀ12 again followed by
stereospecific oxidation.13 Both enantioselective methods,
Rh(I)-catalyzed 1,4-addition of silicon6,8 and Cu(I)-cata-
lyzed 1,4-addition of boron,11 in desymmetrization reac-
tions would complement the existing repertoire of two-
directional polyol syntheses.1ꢀ3 We disclose herein the
stereoselective preparation of 1,3,5-3d,e,14 and 1,4,7-triols
as well as the diastereoselective protection of the 1,3,5-triol
to access the C17ꢀC25 fragment of dermostatin A (1,
Scheme 1, lower).2c,15
At the outset of the project, we sought to learn about the
capability of the chosen catalytic systems to outcompete
substrate control. For this, we tested S configured δ-
silyloxy-substituted R,β-unsaturated carboxyl compounds
Z-2 and E-5 with defined double bond geometries in the
1,4-addition of silicon16 and boron nucleophiles, respec-
tively (Scheme 2).5 As part of the aforementioned iterative
approach,8 we had already observed that, with (R)-binap,
the Rh(I) catalysis yielded the anti diastereomer with dr =
95:5 (Z-2fanti-3, Scheme 2, left); (S)-binap as the ligand
afforded the corresponding syn compound with dr = 99:1
(Z-2fsyn-3). Apparently, there is only a small amount of
influence of the existing stereocenter in Z-2 on the stereo-
chemical course, and a largely catalyst-controlled stereo-
induction provides access to either of the diastereomers.
Combined with subsequent oxidative degradation of the
CꢀSi bond,9 the strategy allows for the formation of anti
and syn diols from the same precursor (anti-3fanti-4 and
syn-3fsyn-4, Scheme 2, left).
Encouraged by these findings, we next turned our
attention to Yun’s Cu(I)-catalyzed conjugate addition of
boron nucleophiles.11 Diastereoselective additions had not
been investigated yet. Control experiments with achiral
R,β-unsaturated carboxyl acceptors showed that, in terms
of stereoselectivity, the E configuration of the alkene is
required. The reaction of E-5 in the presence of (R,Sp)-
josiphos then furnished the anti diastereomer with moder-
ate dr = 89:11 (E-5fanti-6, Scheme 2, right); the syn
diastereomer was obtained employing (S,Rp)-josiphos yet
with the same level of diastereoselection (E-5fsyn-6). The
fact that no matched/mismatched selectivity is observed
here indicates a fully catalyst-controlled transformation
but withimperfect asymmetric induction. Inanalogy to the
previous sequence, oxidation of the CꢀB bond13 also
Scheme 1. Two-Directional Desymmetrization of Prochiral
Carbinols with R,β-Unsaturated Substituents: Access to OH,
OH,OH Building Blocks (m = nꢀ1) with a Chirotopic Atom
(10) For reviews of asymmetric conjugate boryl transfer, see: (a)
€
Schiffner, J. A.; Muther, K.; Oestreich, M. Angew. Chem., Int. Ed. 2010,
49, 1194–1196. (b) Mantilli, L.; Mazet, C. ChemCatChem 2010, 2, 501–
ꢀ
504. (c) Bonet, A.; Sole, C.; Gulyas, H.; Fernandez, E. Curr. Org. Chem.
ꢀ
2010, 14, 2531–2548.
(11) Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145–147.
(12) For further examples with acyclic carboxyl acceptors, see: (a)
ꢀ
ꢀ
Lillo, V.; Prieto, A.; Bonet, A.; Diaz-Requejo, M. M.; Ramırez, J.; Perez,
´
ꢀ
P. J.; Fernandez, E. Organometallics 2009, 28, 659–662. (b) Chen, I-H.;
Kanai, M.; Shibasaki, M. Org. Lett. 2010, 12, 4098–4101. (c) O’Brien,
J. M.; Lee, K.-s.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10630–
10633. (d) Park, J. K.; Lackey, H. H.; Rexford, M. D.; Kovnir, K.;
Shatruk, M.; McQuade, D. T. Org. Lett. 2010, 12, 5008–5011. (e)
ꢀ
Ibrahem, I.; Brestein, P.; Cordova, A. Angew. Chem., Int. Ed. 2011,
50, 12036–12041.
(13) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer: Berlin, 1995; pp 48ꢀ54.
(14) For more protocols on catalytic asymmetric construction of
1,3,5-triols, see: (a) Shepherd, J. N.; Na, J.; Myles, D. C. J. Org. Chem.
1997, 62, 4558–4559. (b) Binder, J. T.; Kirsch, S. F. Chem. Commun.
2007, 4164–4166. (c) Zhang, Z.; Aubry, S.; Kishi, Y. Org. Lett. 2008, 10,
3077–3080. (d) Menz, H.; Kirsch, S. F. Org. Lett. 2009, 11, 5634–5637.
(e) Hassan, A.; Lu, Y.; Krische, M. J. Org. Lett. 2009, 11, 3112–3115. (f)
Kondekar, N. B.; Kumar, P. Org. Lett. 2009, 11, 2611–2614. (g) Kirsch,
S. F.; Klahn, P.; Menz, H. Synthesis 2011, 3592–3603.
(15) (a) Sinz, C. J.; Rychnovsky, S. D. Angew. Chem., Int. Ed. 2001,
40, 3224–3227. (b) Sinz, C. J.; Rychnovsky, S. D. Tetrahedron 2002, 58,
6561–6576.
(16) For the preparation of Me2PhSiꢀBpin, see: (a) Suginome, M.;
Matsuda, T.; Ito, Y. Organometallics 2000, 19, 4647–4649. (b) Summary
of SiꢀB chemistry: Ohmura, T.; Suginome, M. Bull. Chem. Soc. Jpn.
2009, 82, 29–49.
(8) Hartmann, E.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49,
6195–6198.
(9) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599–7662.
Org. Lett., Vol. 14, No. 9, 2012
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Scheme 2. Catalyst vs Substrate Control in the Conjugate Silyl and Boryl Transfers onto δ-Silyloxy-Substituted R,β-Unsaturated
Carboxyl Compoundsa
a Rh(I)-catalyzed conjugate silyl transfer:6,8 [Rh(cod)2]OTf (5.0 mol %), binap (10 mol %), Me2PhSiꢀBpin (2.5 equiv), Et3N (1.0 equiv), 1,4-dioxane/
H2O 10:1, 45 °C. Cu(I)-catalyzed conjugate boryl transfer:11 CuCl (2.0 mol %), NaOt-Bu (3.0 mol %), josiphos (4.0 mol %), pinBꢀBpin (1.1 equiv),
MeOH (2.0 equiv), THF, rt. Oxidation of the CꢀSi bond:9 KBr (1.5 equiv), NaOAc (30 equiv), AcOOH/AcOH 1:1, rt. Oxidation of the CꢀB bond:13
NaBO3 4H2O (5.0 equiv), THF/H2O 1:1, rt.
3
Scheme 3. Enantioselective Access to 1,3,5- and 1,4,7-Triols through Two-Fold Conjugate Addition of Silicon and Boron Nucleophiles
to Bis(R,β-unsaturated) Compoundsa
a See Scheme 2 for reagents and reaction conditions; double the amount of reagents and catalyst was used.
yielded the corresponding anti and syn diols (anti-6fanti-7
and syn-6fsyn-7, Scheme 2, right).
moderate diastereomeric ratio with the meso configuration
for the minor diastereomers syn,syn-11 and anti,anti-11
(not shown). It is only the wrong diastereotopic face
selection in both steps on the same molecule that yields
the undesired enantiomer (ent-syn,anti-11, not shown). As
the probability of this incident is decreased in sequential
functionalizations, enrichment of desired syn,anti-11 is
observed. Again, straightforward oxidative degradation13
enabled the synthesis of the triol syn,anti-10 in good
chemical yield (syn,anti-11f syn,anti-10).
In light of these stereoselectivities, we anticipated ε-
silyloxy-substituted homologues Z,Z-12 and E,E-12 to
be an equally effective entry into the asymmetric synthesis
of 1,4,7-triols (Scheme 3). Indeed, Z,Z-12 performed well
in the Rh(I) catalysis,6,8 and doubly silylated syn,anti-13
was obtained with superbstereocontrol (Z,Z-12fsyn,anti-
13, Scheme 3, upper).17 Subsequent oxidation9 completed
the sequence to yield the stereodefined 1,4,7-triol syn,anti-
14 (syn,anti-13fsyn,anti-14). Similarly, substrate E,E-12
was subjected to the boryl transfer11 (E,E-12fsyn,anti-15,
Scheme 3, lower). This time, with the remote prochiral
With these promising results, we were curious to apply
these asymmetric 1,4-additions to the two-fold function-
alization of bis(R,β-unsaturated) acceptors. We were then
delighted to see that the Rh(I)-catalyzed silyl transfer6,8
onto the prochiral δ-silyloxy-substituted Z,Z-8 afforded
desired syn,anti-9 essentially as a single stereoisomer17 in
good chemical yield (Z,Z-8fsyn,anti-9, Scheme 3, upper).
Its conversion using standard oxidation conditions9 made
triol syn,anti-10 with a 1,3,5-relationship of the hydroxy
groups available (syn,anti-9fsyn,anti-10). The Cu(I)-cat-
alyzed borylation11 was applied to isomeric acceptor E,E-
8, and syn,anti-11 was formed with 99% ee and dr = 87:13
(E,E-8fsyn,anti-11, Scheme 3, lower).17 As predicted on
the basis of previous experiments (cf. Scheme 2, right), the
individual steps do not proceed with perfect differentiation
of the diastereotopic faces, and that is reflected in the
(17) Diastereomeric ratios were determined by either GLC analysis
or NMR spectroscopy. Minor stereoisomers were assigned by compar-
ison with independently prepared samples using racemic ligands.
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Org. Lett., Vol. 14, No. 9, 2012

center, only a negligible amount of the meso diastereomers
syn,syn-15 and anti,anti-15 (not shown) was formed.17
With that improved diastereofacial discrimination, syn,
anti-15 was formed with >99% ee almost as a single
diastereomer. After oxidative degradation13 (syn,anti-
15fsyn,anti-14), the boron-based sequence arrives at the
same 1,4,7-triol as the silicon-based strategy (syn,anti-
13fsyn,anti-14).
Scheme 4. Terminus Differentiation through Diastereoselective
Acetalization: Synthesis of the C17ꢀC25 Fragment of 1
After conversion of the prochiral precursors into chiral
compounds, one challenge remains. Unlike with C2-sym-
metric molecules, the termini of pseudo-C2-symmetric
compounds are not equivalent, i.e., not homotopic. To
break the symmetry with another functional group manip-
ulation, one terminus mustbe selectedover the other, inthe
course of which the chirotopic atom will become
stereogenic.1b For pseudo-C2-symmetric polyols, that dif-
ferentiation is achieved by diastereoselective acetaliza-
tion.18 To demonstrate the utility of our approach, we
performed such an acetalization on a polyol made by the
above strategy. To this end, the terminal carboxyl groups
of syn,anti-9 were reduced, and the primary alcohols were
protected as pivalates (syn,anti-9f16, Scheme 4, upper).
Oxidative degradation of the CꢀSi bonds afforded ortho-
gonally protected 1,3,5,7,9-pentol 17 in decent yield
(16f17). Finally, removal of the TBS group at the
central hydroxy group was followed by acetalization
of the syn-configured hydroxy groups in 18 to afford
compound 19 as the major diastereomer (17f18f19).
The enantiomer of this fragment with different protect-
ing groups (cf. 20, Scheme 4, lower) is an intermediate
in a recent total synthesis of dermostatin A (1) by
Sammakia.2c
The present work compares indirect asymmetric con-
jugate hydration protocols,5 that is enantioselective 1,4-
additions of silicon and boron nucleophiles followed
by oxidation, in a two-directional desymmetrization of
prochiral bis(R,β-unsaturated) acceptors. Both methods
exert excellent catalystcontrol, butthesilylationissuperior
to the borylation in terms of asymmetric induction. In
turn, the oxidative degradation of the Cꢀelement bond is
more practical for the CꢀB than the CꢀSi bond. Yields
are generally higher in the borylation/oxidation sequence.
By this general approach, stereodefined 1,3,5- and 1,4,7-
triols become accessible. The differentiation of a pseudo-
C2-symmetric building block is achieved by diastereoselec-
tive acetalization as shown in the preparation of the
enantiomeric C17ꢀC25 fragment of dermostatin A (1).
Acknowledgment. This research was supported by the
Deutsche Forschungsgemeinschaft (Oe 249/3-2) and the
Fonds der Chemischen Industrie (predoctoral fellowship
to E.H., 2009ꢀ2011). M.O. is indebted to the Einstein
Foundation (Berlin) for an endowed professorship. We
thank Monika Ulrich (TU Berlin) for her experimental
contributions.
Supporting Information Available. Detailed starting
material syntheses, general procedures, characterization
1
data, and H and 13C NMR spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) For selected examples of terminus differentiation through dia-
stereoselective acetalization, see: (a) Reference 2a. (b) Reference 2c.
(c) Reference 14a. (d) Shepherd, J. N.; Myles, D. C. Org. Lett. 2003, 5,
1027–1030.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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