Synthesis of protected chiral vicinal diaminoalcohols by diastereoselective intramolecular benzylic substitution from bistrichloroacetimidates

Article abstract of DOI:10.1021/ol0627202

(Chemical Equation Presented) An efficient synthesis of chiral dihydrooxazines (2) from 1-aryl-2-amino-propane-1,3-diols (1) via the corresponding bistrichloroacetimidate intermediates has been developed. In this transformation, one trichloroacetimidate a

Full text of DOI:10.1021/ol0627202

ORGANIC
LETTERS
2007
Vol. 9, No. 2
247-250
Synthesis of Protected Chiral Vicinal
Diaminoalcohols by Diastereoselective
Intramolecular Benzylic Substitution
from Bistrichloroacetimidates
Christophe Rondot, Pascal Retailleau, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex,
France
zhu@icsn.cnrs-gif.fr
Received November 7, 2006
ABSTRACT
An efficient synthesis of chiral dihydrooxazines (2) from 1-aryl-2-amino-propane-1,3-diols (1) via the corresponding bistrichloroacetimidate
intermediates has been developed. In this transformation, one trichloroacetimidate acts as a leaving group and the other acts as a nucleophile.
The cyclization proceeds through an SN1 mechanism to provide trans-dihydrooxazines with complete diastereoselectivity irrespective of the
absolute configuration of the benzylic alcohol. The transformation of 2 into other selectively protected aminodiols is also documented.
Trichloroacetimidate is known to be a good leaving group
under acidic conditions especially if the putative carbenium
intermediate is stabilized by a neighboring heteroatom, aryl,
allyl, or oxyallyl group, etc.1 Thus, O-glycosyl trichloroace-
timidates are efficient glycosyl donors for the synthesis of
glycoconjugates,2 whereas benzyl trichloroacetimidates are
proven to be versatile benzylation reagents for hydroxy
groups under acidic conditions (eq 1, Scheme 1).3 On the
other hand, the nitrogen atom of trichloroacetimidates can
also act as an efficient nucleophile for intramolecular ring
opening of halonium salts,4 epoxides,5 and dioxolanyliums
(eq 2, Scheme 1).6 The Overman rearrangement,7 a [3,3]-
sigmatropic rearrangement that combines the dual reactivities
Scheme 1. Trichloroacetimidate as a Leaving Group and as a
Nucleophile
(1) Abdel-Rahman, A. A.-H.; Winterfeld, G. A.; Takhi, M.; Schmidt,
R. R. Eur. J. Org. Chem. 2002, 713-717 and references cited therein.
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235. (b) Roussel, F.; Knerr, L.; Grathwohl, M.; Schmidt, R. R. Org. Lett.
2000, 2, 3043-3046. (c) Zhang, J.; Schmidt, R. R. Synlett 2006, 1729-
1733.
(3) (a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240-1241. (b) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc.,
Perkin Trans. 1 1985, 2247-2250. (c) Zhang, J.; Schmidt, R. R. Synlett
2006, 1729-1733.
(4) (a) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J.
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S.; Youn, J.-H. J. Chem. Soc., Chem. Commun. 2000, 227-228 and
references therein.
10.1021/ol0627202 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/21/2006

of trichloroacetimidates, has also found widespread applica-
tion in organic synthesis (eq 3). Interestingly, the transforma-
tion shown in eq 4 (Scheme 1) wherein one trichloroace-
timidate acts as a nucleophile while the other acts as a leaving
group has rarely been investigated. Aside from the stereo-
chemical issue, a potential pitfall of this otherwise attractive
approach is the regioselectivity of the reaction. Indeed, two
examples reported in the literature involving intramolecular
vinylogous Schmidt glycosidation showed disparate regio-
selectivities.8,9 We reasoned that by varying the electronic
nature of the R and R1 groups we should be able to push the
reaction to proceed through an SN1 mechanism and conse-
quently to control the regioselectivity of the cyclization by
modulating the relative stability of the incipient carbenium
intermediate. Because the resulting oxazoline (five-membered
ring) or oxazine (six-membered ring) is easily hydrolyzed,
this route would constitute an efficient way to synthesize
amino alcohols and derivatives thereafter from 1,2- or 1,3-
diols. Nicolaou and co-workers have recently reported an
elegant synthesis of sulfamidate from styrene-derived 1,2-
diols using the Burgess reagent on the basis of the same
principle.10,11
Scheme 3. Synthesis of 1-Aryl-2-aminopropane-1,3-diols 1
and Garner’s aldehyde 4 mediated by methyl magnesium
chloride afforded the syn adduct 5 in excellent yield and
diastereoselectivity (cf. Supporting Information for details).15
The syn selectivity was taken for granted on the basis of
Casiraghi’s work and was confirmed by X-ray analysis in
our related studies.16 Allylation of phenol followed by
cleavage of oxazolidine with p-toluenesulfonic acid generated
the desired amino diol 1 (Scheme 3).
To our delight, attempted synthesis of bistrichloroacetimi-
dates by reaction of aminodiol 1a with 3 equiv of trichlo-
roacetonitrile in dichloromethane in the presence of DBU
afforded directly the trans-dihydrooxazine 2a in 62% yield
(Scheme 4). The hypothetic bistrichloroacetimidate was not
isolable in this case. The structure of 2a was assigned without
In connection with our ongoing project, we were interested
in the synthesis of chiral diamines.12,13 As a continuation of
this research program, we report in this letter an efficient
synthesis of oxazine 2 from readily accessible 1-aryl-2-
amino-propane-1,3-diol (1) via a bistrichloroacetimidate
intermediate and document that the overall process is highly
regio- and stereoselective irrespective of the absolute con-
figuration of the benzylic alcohol (Scheme 2).14
1
ambiguity by X-ray analysis. The H NMR spectrum of 2a
displayed a coupling constant (JH4-H5 ) 5.6 Hz) characteristic
of the trans relationship of these two protons.4b,c By applying
the same one-pot protocol, compounds 2b and 2c were
prepared from the corresponding aminodiols with complete
regio- and stereoselectivity.
When diol 1d was reacted with trichloroacetonitrile in
dichloromethane in the presence of DBU, the corresponding
bistrichloroacetimidate 6d was isolated in 50% yield (Scheme
5). Although 6d was not very stable, it was isolated by
column chromatography and was fully characterized. In the
presence of a catalytic amount of methanesulfonic acid (0.05
equiv of MeSO3H in CH2Cl2, C ) 0.03 M), 6d cyclized
Scheme 2. Synthesis of Diaminoalcohol by Intramolecular
Cyclization of Bistrichloroacetimidate
(10) (a) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella,
M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834-838. (b) Nicolaou,
K. C.; Snyder, S. A.; Nalbandian, A. Z.; Longbottom, D. A. J. Am. Chem.
Soc. 2004, 126, 6234-6235. (c) Nicolaou, K. C.; Snyder, S. A.; Longbottom,
D. A.; Nalbandian, A. Z.; Huang, X. Chem.-Eur. J. 2004, 10, 5581-5606.
(11) Rinner, U.; Adams, D. R.; Santos, M. L. D.; Abboud, K. A.;
Hudlicky, T. Synlett 2003, 1247-1252.
The required amino diol 1 was synthesized as shown in
Scheme 3. Phenolic aldol condensation between phenol 3
(5) (a) Bernet, B.; Vasella, A. Tetrahedron Lett. 1983, 24, 5491-5494.
(b) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J.; Fischer, P.
Synthesis 1989, 256-261. (c) Hatakeyama, S.; Matsumoto, H.; Fukuyama,
H.; Mukugin, Y.; Irie, H. J. Org. Chem. 1997, 62, 2275-2279. (d) Green,
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Kakinuma, K. J. Chem. Soc., Perkin Trans. 1 2001, 569-577. (f) Wang,
B.; Yu, X.-M.; Lin, G.-Q. Synlett 2001, 904-906. (g) Brennan, C. J.;
Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003, 44, 8757-8760. (h)
Lu, X.; Bittman, R. Tetrahedron Lett. 2006, 47, 825-827.
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(7) Overman, L. E. Acc. Chem. Res. 1980, 13, 218-224. For a metal-
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J. Am. Chem. Soc. 2003, 125, 12412-12413.
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1995, 117, 552-553. (b) Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky,
S. J.; Chou, T. C.; Ballas, L. M. J. Am. Chem. Soc. 1996, 118, 2825-
2842.
(9) Langner, M.; Laschat, S.; Grunenberg, J. Eur. J. Org. Chem. 2003,
1494-1499.
(12) For reviews, see: (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew.
Chem., Int. Ed. 1998, 37, 2580-2627. (b) Reetz, M. T. Chem. ReV. 1999,
99, 1121-1162.
(13) For diastereoselective and stereodivergent three-component phenolic
Mannich reactions, see: Rondot, C.; Zhu, J. Org. Lett. 2005, 7, 1641-
1644.
(14) The bistrichloroacetimidates of olefinic 1,3-diols and olefinic 1,2-
diols have been prepared and used in iodine-promoted cyclization. Under
these conditions, these bistrichloroacetimidates displayed completely dif-
ferent reactivity from that shown in the present study. See: (a) Kang, S.
H.; Kim, J. S.; Youn, J.-K. Tetrahedron Lett. 1998, 39, 9047-9050. (b)
Kang, S. H.; Kim, C. M.; Youn, J.-K. Tetrahedron Lett. 1990, 40, 3581-
3582.
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4922.
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Commun. 2003, 2896-2897. (b) Chen, X.; Chen, J.; De Paolis, M.; Zhu, J.
J. Org. Chem. 2005, 70, 4397-4408.
248
Org. Lett., Vol. 9, No. 2, 2007

Scheme 4. One-Pot Synthesis of Dihydrooxazines 2a-c
Figure 1. Yields of dihydrooxazines 2e-i from a two-step
synthesis.
was synthesized by reacting the diol with 1 equiv of
trichloroacetonitrile. When 8 was submitted to the same
reaction conditions as those described for 6d, the 1,3-dioxane
9, instead of the desired oxazine, was produced (Scheme 6).
smoothly to afford the trans-dihydrooxazine 2d in 71% yield.
Lewis acids such as BF3‚OEt2 and Et2AlCl were less effective
as catalysts for this reaction. It is interesting to note that the
alternative cyclization mode leading to oxazolidinone 7 was
Scheme 6. Cyclization of Hydroxy Trichloroacetimidate
Scheme 5. Two-Step Synthesis of Dihydrooxazine 2d
The intramolecular nucleophilic addition of the hydroxy
group to the protonated imine (6-exo-trig cyclization) could
account for the formation of dioxane 9. We emphasize that
the reaction is highly diastereoselective due to the favorable
steric and stereoelectronic effects to generate only one single
isomer 9 whose structure was determined by X-ray analysis
(cf. Supporting Information).
The inversion of stereochemistry at the benzylic center
was observed from 1 to 2 in all cases examined. To probe if
the substitution reaction went through the SN2 mechanism
as these results might suggest, an anti-aminodiol 10 was
synthesized by a Ti-mediated phenolic aldol condensation
process (Scheme 7).15 When 10 was submitted to reaction
conditions identical to those described for its syn diastere-
omer, the same trans-dihydrooxazine 2a was isolated in 74%
yield. These results indicated that the cyclization might
proceed through an SN1 rather than an SN2 mechanism.
Supposing that the reaction went through an ortho-quinone
methide intermediate 11,18 the stereochemical outcome may
be explained on the basis of conformational analysis.
Considering the relative stability of the four conformers
(Scheme 8), 11D with all substituents in the pseudoequatorial
not observed indicating the higher nucleophilicity of the
trichloroacetimidate over the tert-butyloxycarbonyl function
under these reaction conditions.17 The scope of this two-
step process was found to be quite general, and other
dihydrooxazines synthesized are listed in Figure 1. At the
present time, we have no clear-cut explanation on the
different reactivity of the bistrichloroacteimidates derived
from 1a-c and 1d-i.
To evaluate the importance of using the bistrichloroace-
timidate as the cyclization precursor, the benzyl alcohol 8
(17) De Paolis, M.; Blankenstein, J.; Bois-Choussy, M.; Zhu, J. Org.
Lett. 2002, 4, 1235-1238.
Org. Lett., Vol. 9, No. 2, 2007
249

Scheme 7. Stereochemical Issue of the Cyclization
Scheme 9. Derivatization of Dihydrooxazine 2a
position may predominate over others. Cyclization by a
6-exo-trig mode afforded then the observed trans-dihydroox-
azine.
the imidazolidinone 12 in 95% yield. On the other hand,
stirring a solution of 2a in CH2Cl2 and TFA (v/v ) 5:1) at
room temperature generated the oxazolidinone 13 in quan-
titative yield. The structure of 13 was confirmed by X-ray
analysis (cf. Supporting Information).
Scheme 8. Stereochemical Consideration
In conclusion, we have developed an efficient synthesis
of the selectively protected diamino alcohol unit that is of
considerable interest in terms of both synthetic application
and catalyst design.19 The key to our approach is the
exploitation of the dual reactivities of bistrichloroacetimi-
dates. The application of this chemistry to the total synthesis
of bioactive natural products such as bioxalomycin20 is in
progress.
Acknowledgment. Financial support from the CNRS and
a doctoral fellowship from this institute to C.R. are gratefully
acknowledged.
Although the dihydrooxazine can be hydrolyzed under
acidic conditions, we have found two interesting transforma-
tions that lead to the selectively protected form of the diamino
alcohol (Scheme 9). Thus, heating to reflux a methanol
solution of 2a in the presence of NaOH (20 equiv) afforded
Supporting Information Available: Experimental details
and physical data for compounds 1-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0627202
(18) (a) For a recent comprehensive review in the field, see: Van De
Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367-5405. (b) For
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Am. Chem. Soc. 2006, 128, 87-89. (c) El Ka¨ım, L.; Grimaud, L.; Oble, J.
Org. Biomol. Chem. 2006, 4, 3410-3413 and references cited therein.
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(20) For a recent comprehensive review in the field, see: Scott, J. D.;
Williams, R. M. Chem. ReV. 2002, 102, 1669-1730.
250
Org. Lett., Vol. 9, No. 2, 2007