Expanding the scope of the asymmetric anti-aldol addition of chiral N-amino cyclic carbamate hydrazones

Article abstract of DOI:10.1016/j.tetlet.2013.07.140

An asymmetric anti-aldol addition process of ketone-derived donors that is not limited by the structure of the ketone is described. This is achieved by merging the enantioselective α,α-bisalkylation of N-amino cyclic carbamate (ACC) hydrazones with the asymmetric anti-aldol addition of ACC hydrazones. The products of this process are obtained with essentially perfect stereoselectivity. Using this procedure it is possible to gain access to ketone-based anti-aldol addition products that are inaccessible in a controlled sense via direct aldol methods.

Full text of DOI:10.1016/j.tetlet.2013.07.140

Tetrahedron Letters 54 (2013) 5470–5472
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Expanding the scope of the asymmetric anti-aldol addition of chiral
N-amino cyclic carbamate hydrazones
⇑
John D. Knight, Don M. Coltart
Department of Chemistry, University of Houston, Houston, TX 77204-5003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric anti-aldol addition process of ketone-derived donors that is not limited by the structure of
Received 17 July 2013
Accepted 25 July 2013
Available online 1 August 2013
the ketone is described. This is achieved by merging the enantioselective
a,a-bisalkylation of N-amino
cyclic carbamate (ACC) hydrazones with the asymmetric anti-aldol addition of ACC hydrazones. The
products of this process are obtained with essentially perfect stereoselectivity. Using this procedure it
is possible to gain access to ketone-based anti-aldol addition products that are inaccessible in a controlled
sense via direct aldol methods.
Keywords:
anti-Aldol addition
Asymmetric synthesis
Alkylation
Ó 2013 Elsevier Ltd. All rights reserved.
Ketone
Hydrazone
The asymmetric anti-aldol addition of ketone donors is an
important synthetic transformation.1 Remarkably, despite this,
and in contrast to its syn-counterpart,2 no general way of conduct-
ing the anti-aldol addition of ketone donors is available that is not
limited by the structure of the ketone that can be used.1 We re-
tance of the anti-selective ketone aldol addition, the ability to con-
duct it in a manner that is independent of the structure of the
ketone is extremely desirable.
As mentioned, we have developed an approach to the enantio-
selective a,a-bisalkylation of ketones via chiral N-amino cyclic car-
cently described two new methods for the asymmetric
alization of ketones through the use of N-amino cyclic carbamate
(ACC) hydrazones, namely ACC
-bisalkyation3 and ACC anti-al-
a
-function-
bamate (ACC) hydrazones3 (Scheme 1a).9 This method has several
desirable attributes. For instance, the auxiliaries are both easily
introduced into and removed from ketones, with nearly quantita-
tive recovery. Deprotonation is rapid and alkylation proceeds with
excellent regio- and stereoselectivity, as well as yield. Given these
traits, we were curious about the possibility of extending the use of
this alkylation method to the aldol addition. Our investigations
along these lines led to the development of an unusual, thermody-
namically controlled anti-aldol addition reaction.4 In that study,
the symmetrical ketone, 3-pentanone, was used to prepare the
hydrazone substrate (3), which was then combined with a variety
of aldehydes to produce, following in situ benzylation and then
auxiliary removal, the corresponding anti-aldol products (4) as a
single stereoisomer (Scheme 1b). To further probe this method,
we wanted to investigate the possibility of extending it to the syn-
thesis of even more structurally challenging anti-aldol products. In
particular, we wished to access aldol products that, structurally,
would correspond to those obtained by the regiocontrolled addi-
a,a
dol addition4 (Scheme 1). In what follows, we demonstrate that
by merging these two methods, the limitations associated with
current ketone-based aldol reaction regarding the structure of
the ketone that may be used can be overcome. Consequently, ac-
cess to ketone-based aldol addition products that have previously
been inaccessible in a controlled manner via direct aldol methods
becomes possible.
Over the years, a few anti-selective aldol additions have been
reported.5 In the early 1990s, Heathcock and Patterson indepen-
dently developed highly effective anti-selective methods for cer-
tain chiral, nonracemic
a
-, and b-substituted ketones.6 More
recently, some achiral ketones have been shown to undergo anti-
aldol additions in the presence of organocatalysts.7 Unfortunately,
the latter transformations are also inherently limited with regard
to the structure of the ketone that may be used. Specifically, only
ketones for which regioselectivity of deprotonation is not a factor
(e.g., symmetrical ketones, aryl alkyl ketones, etc.) are viable sub-
strates. Previous attempts to use chiral auxiliaries for ketone-based
aldol additions have met with variable success.8 Given the impor-
tion of nonsymmetrical ketones having both
a
- and a0-protons
(e.g., 3-hexanone) to aldehydes. Despite the considerable effort
that has been devoted to the study of aldol chemistry over the
years, no such method has yet been reported to achieve this.
In order to access these more structurally complex compounds,
we planned to use a modified version of our enantioselective ACC
⇑
Corresponding author.
E-mail address: dcoltart@uh.edu (D.M. Coltart).
a,a
-bisalkylation method (Scheme 1a).3 In that method, complex
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.140

J. D. Knight, D. M. Coltart / Tetrahedron Letters 54 (2013) 5470–5472
5471
Scheme 3. Synthesis of nonsymmetrical ketone-based anti-aldol product 14.
Scheme 1. Reagents and conditions: (a) enantioselective ACC
Asymmetric ACC anti-aldol addition.
a,a-bisalkylation; (b)
product 13 in excellent yield, and as a single stereoisomer. Auxil-
iary removal was achieved in excellent yield by treatment with
p-TsOHꢁH2O in acetone, and occurred without epimerization to
give b-benzyloxy ketone 14 (see Scheme 3).
In a similar way, the allyl- and prenyl-containing anti-aldol
products (17 and 20, respectively) were obtained in very good
overall yield (Scheme 4).11 In each case, the alkylation step pro-
ceeded to give a single regioisomer (15 and 18, respectively), and
the aldol process produced a single b-benzyloxy ketone stereoiso-
mer (17 and 20, respectively).
Given the expansive body of literature addressing the chemical
manipulation of ketones, the methyl ketones (cf. 14, 17, 20) ob-
tained from this process are poised for further elaboration in
numerous synthetically useful ways. For example, simple alkyl-
ation at the a0-position could be used to provide additional struc-
tural diversity. To demonstrate this, methyl ketone 17 was
induced-syn deprotonation (CIS-D) is used to direct removal of the
proton on the same side of the carbon–nitrogen double bond as the
ACC auxiliary (Scheme 2, 5 ? 6). Alkylation of the resulting config-
urationally stable azaenolate (6) then gives exclusively the
ated product (7). Repetition of this process provides the
bisalkylated hydrazone having a new stereogenic center at the
position. Auxiliary removal then gives the desired
ketone enantiomer (9). If our recently developed aldol addition
reaction4 could be used in place of the second alkylation step, then
it should be possible to gain access to the more structurally chal-
lenging anti-aldol structures desired (8 ? 10).
To test this process, hydrazone 1 was prepared by the conden-
sation of ACC auxiliary 11 and acetone. Treatment of 1 with LDA at
ꢀ78 °C, followed by ethyl iodide gave compound 12 as a single
double bond diastereomer.3,10 With this nonsymmetrical hydra-
zone 12 in hand, we were able to try the anti-aldol addition
process. Thus, 12 was treated with LDA at ꢀ78 °C, benzaldehyde
was then added, the cold bath was removed and the mixture was
stirred for 2 h, at which point benzyl iodide was added. As hoped,
this one-pot process gave rise to the O-benzylated anti-addition
a-alkyl-
a,a
-
a
-
a
,a-bisalkylated
Scheme 2. Asymmetric ACC
alkylation/anti-aldol addition via complex induced syn-deprotonation (CIS-D).
a
,
a
-bisalkylation and proposed asymmetric ACC
Scheme 4. Synthesis of nonsymmetrical ketone-based anti-aldol products 17 and
20.

5472
J. D. Knight, D. M. Coltart / Tetrahedron Letters 54 (2013) 5470–5472
2. (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129;
(b) Evans, D. A.; Reiger, D. L.; Biliodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991,
113, 1047–1049; (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 111–115; (d) Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 77–81; (e)
Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591–594; (f) Crimmins, M.
T.; Christie, H. S.; Hughes, C. O. Org. Synth. 2011, 88, 364; (g) Paterson, I.; Lister,
M. A.; McClure, C. K. Tetrahedron Lett. 1986, 27, 4787–4790; (h) Paterson, I.;
McClure, C. K. Tetrahedron Lett. 1987, 28, 1229–1232; (i) Paterson, I.; Goodman,
J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121–7124; (j) Paterson, I.; Goodman,
J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.; Norcross, R. D. Tetrahedron
1990, 46, 4663–4684.
Scheme 5. Prenylation of methyl ketone 17.
treated with LDA followed by prenyl bromide, which provided
compound 21 in excellent yield (Scheme 5). Addition of HMPA to
the reaction mixture after deprotonation with LDA but before the
addition of prenyl bromide was necessary to achieve a high yield
of product. Significantly, a compound such as 21 could not be ac-
cessed in a stereo- or regiocontrolled manner via conventional ke-
tone-based aldol additions.
In conclusion, we have developed an asymmetric anti-aldol
addition of ketone-derived donors to aldehydes through the use
of ACC hydrazones. Unlike other anti-selective asymmetric ke-
tone-based aldol reactions, the present transformation is not lim-
ited by the structure of the ketone that can be used. As such, it
enables the preparation of unsymmetrical ketone aldol products
that would be very challenging or impossible to prepare in a con-
trolled manner using established methods.
3. Wengryniuk, S. E.; Lim, D.; Coltart, D. M. J. Am. Chem. Soc. 2011, 133, 8714–
8720.
4. Knight, J. D.; Coltart, D. M. Chem. Commun. 2013, 49, 7495–7497.
5. See, for example: (a) Kotani, S.; Hashimoto, S.; Nakajima, M. Synlett 2006,
1116–1118; (b) Swiss, K. A.; Choi, W.-B.; Liotta, D. C. J. Org. Chem. 1991, 56,
5978–5980; (c) Wei, H.-X.; Jasoni, R. L.; Shao, H.; Hu, J.; Pare, P. W. Tetrahedron
2004, 60, 11829–11835; (d) Mahrwald, R. Tetrahedron 1995, 51, 9015–9022.
6. (a) Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H. J. Org.
Chem. 1991, 56, 2499–2506; (b) Paterson, I.; Wallance, D.; Velazquez, S. M.
Tetrahedron Lett. 1994, 48, 9083–9086; (c) Paterson, I.; Wallace, D. J.; Cowden,
C. J. Synthesis 1998, 639–652. See also: Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Rieger, D. J. J. Am. Chem. Soc. 1995, 117, 9073–9074..
7. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2305–2396;
(b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386–7387; (c) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–575; (d) List, B. Tetrahedron
2002, 58, 5573–5590; (e) Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Mi, A.-Q.; Jiang, Y.-
Z.; Gong, L.-Z. J. Am. Chem. Soc. 2005, 127, 9285–9289; (f) Sakthivel, K.; Notz,
W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260–5267; (g) Tang, Z.;
Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5755–5760; (h) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi,
J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 5527–5529; (i)
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799; (j)
Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc.
1999, 121, 4168–4178.
8. (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D. Tetrahedron 2002, 58,
2253–2329; (b) Eichenauer, H.; Friedrich, E.; Lutz, W.; Enders, D. Angew. Chem.,
Int. Ed. 1978, 17, 206–207; (c) Enders, D.; Eichenauer, H.; Pieter, R. Chem. Ber.
1979, 112, 3703–3714; (d) Enders, D.; Dyker, H.; Raabe, G. Angew. Chem., Int. Ed.
Engl. 1993, 32, 421–423; (e) Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110,
1386–1434; (f) McGlacken, G. P.; Breeden, S. W. Tetrahedron: Asymmetry 2005,
16, 3615–3618; (g) Smith, A. B., III; Ishiyama, H.; Cho, Y. S.; Ohmoto, K. Org. Lett.
2001, 3, 3967–3970.
9. For further details of asymmetric ACC alkylation, see: (a) Lim, D.; Coltart, D. M.
Angew. Chem., Int. Ed. 2008, 47, 5207–5210; (b) Krenske, E. H.; Houk, K. N.; Lim,
D.; Wengryniuk, S. E.; Coltart, D. M. J. Org. Chem. 2010, 75, 8578–8584.
10. Synthesis of 12 via condensation of 2-pentanone and the ACC auxiliary (11) is
possible but would be expected to lead preferentially to the undesired (E)-
diastereomer, which cannot be used for the intended regiocontrolled aldol
addition.
Acknowledgment
We are grateful to the NSF (NSF 1012287) and the University of
Houston for support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.140.
References and notes
1. (a) Palomo, C.; Oiarbide, M.; Garcia, J. Chem. Soc. Rev. 2004, 33, 65–75; (b)
Geary, L.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131–173.
11. See the Supplementary data for details.