WO2003066549A2

WO2003066549A2 - Synthesis of sulfamidates

Info

Publication number: WO2003066549A2
Application number: PCT/US2003/003788
Authority: WO
Inventors: Kyriacos C. Nicolaou; Scott. A Snyder; Xianhai Huang
Original assignee: The Scripps Research Institute
Priority date: 2002-02-07
Filing date: 2003-02-07
Publication date: 2003-08-14
Also published as: WO2003066549A3; AU2003217354A8; AU2003217354A1

Abstract

A regio- and stereoselective two-stage synthesis of β-aminoalcohols employs a key transformation, viz., the creation of a cyclic sulfamidate from a precursor diol, mediated by Burgess-type reagents. The generality and scope of this approach is underscored by the considerable number and variety of substrates which display high levels of selectivity in the process. As such, this method provides facile access to compounds for use in myriad applications, whether as chiral ligands to perform asymmetric synthesis or as molecular probes to explore problems in chemical biology.

Description

SYNTHESIS OF SULFAMIDATES

Description

Technical Field:

The invention relates to processes and reagents employable for synthesizing sulfamidates. More particularly, the invention relates to regio- and stereoselective processes for synthesizing sulfamidates from 1 ,2-diols and for converting 1 ,2 diols into β-aminoalcohols and to novel Burgess-type reagents that are employable within these processes.

Background:

Chiral β-aminoalcohols have become an increasingly targeted functional motif in organic synthesis due to their ubiquity in biologically active compounds, as well as their value as ligands in asymmetric synthesis (For selected reviews on the synthesis and applications of 1 ,2-aminoalcohols, see: T. Kunieda, T. Ishizuka in Studies in Natural Products Chemistry, Vol. 12 (Ed.: Atta-ur-Rahman), Elsevier, New York, 1993, p. 411 ; Golebiowski, A.; Jurczak, J. Synlett 1993, 241 - 245; Ohfune, Y. Ace. Chem. Res. 1992, 25, 360 - 366; Yokomatsu, T.; et al. Heterocycles 1992, 33, 1051 - 1078; Reetz, M. T. Angew. Chem. 1991 , 103, 1559 - 1573; Angew. Chem. Int. Ed. Engl. 1991 , 30, 1531 - 1545. For additional reviews of this important area, see: Corey, E. J.; Helal, C. J. Angew. Chem. 1998, 110, 2092 - 2118; Angew. Chem. Int. Ed. 1998, 37, 1986 - 2012; Wallbaum, Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475 - 1504; Noyori, R.; Kitamura, M. Angew. Chem. 1991, 103, 34 - 55; Angew. Chem. Int. Ed. Engl. 1991 , 30, 49 - 69; Singh, V. K. Synthesis 1991 , 605 - 617. For some recent papers employing c/s-1 ,2-aminoalcohols, see: Di Simone, B.; et al. Tetrahedron: Asymmetry 1995, 6, 301 - 306; Hong, Y.; et al. Tetrahedron Lett. 1994, 35, 6631 - 6634.). Presently, several powerful methods exist to enantioselectively create such synthons, foremost of which is Sharpless' osmium-catalyzed asymmetric aminohydroxylation (AA) (Li, G.; et al. Angew. Chem. 1996, 108, 449 - 452; Angew. Chem. Int. Ed. Engl. 1996, 35, 451 - 454; Li, G.; Sharpless, K. B. Acta Chem. Scand. 1996, 35, 451 - 454). Although the utility of this reaction is unquestionable, variable regio- and enantioselectivity is still observed in certain structural types despite significant optimization of reaction conditions (For selected examples of recent papers in the AA field, see: Demko, Z. P.; et al. Org. Lett. 2000, 2, 2221 - 2223; Goossen, L. K.; et al. Angew. Chem. 1999, 111, 1149 - 1152; Angew. Chem. Int. Ed. 1999, 38, 1080 - 1083; Reddy, K. L; et al. Tetrahedron Lett. 1998, 39, 3667 - 3670; Bruncko, M.; et al. Angew. Chem. 1997, 709, 1580 - 1583; Angew. Chem. Int. Ed. Engl. 1997, 36, 1483 - 1486. For an alternate and useful preparation of chiral 1 ,2-aminoalcohols starting from substrates other than olefins, see: Ender, D.; Reinhold, U. Angew. Chem. 1995, 107, 1332-1334; Angew. Chem. Int. Ed. Engl. 1995, 34, 1219-1222.).

Sulfamidates are typically prepared from chiral β-aminoalcohol starting materials in several synthetic operations (based on the number of protecting group manipulations required), and are then utilized to generate a diverse array of functionality based on the established ability of this synthon to undergo highly selective reactions with 0-, S-, N-, C-, and F-based nucleophiles, yielding compounds of general structure IV (Wei, L.; Lubell, W. D. Org. Lett. 2000, 2, 2595 - 2598; Boulton, L. T.; et al. J. Chem. Soc, Perkin Trans. 1 1999, 1421 - 1429; Ok, D.; et al. Tetrahedron Lett. 1999, 40, 3831 - 3834; Kim, B. M.; So, S. M. Tetrahedron Lett. 1998, 39, 5381 - 5384; Aguilera, B.; et al. Tetrahedron 1997, 53, 5863 - 5876; Van Dort, M. E.; et al. J. Med. Chem. 1995, 38, 810 - 815; Andersen, K. K.; Kociolek, M. G. J. Org. Chem. 1995, 60, 2003 - 2007; Okuda, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 4585 - 4586; Andersen, K. K.; et al. J. Org. Chem. 1991 , 56, 6508 - 6516; White, G. J.; Garst, M. E. J. Org. Chem. 1991 , 56, 3177 - 3178; Baldwin, J. E.; et al. Tetrahedron: Asymmetry 1991 , 1, 881 - 884; Alker, D.; et al. Tetrahedron: Asymmetry 1991 , 7, 877 - 880; Lyle, T. A.; et al. J. Am. Chem. Soc. 1987, 709, 7890 - 7891 ).

What is needed is alterative methods for synthesizing cyclic sulfamidates and chiral β-aminoalcohols . Summary:

One aspect of the invention is directed to a Burgess-type reagent represented by the following structure:

In the above structure, -C(0)OR is a carbamate protecting group, with a proviso that R is not methyl, ethyl, or polyethylene glycol. In a preferred embodiment, R is selected from alkyl, allyl, alkenyl, haloalkyl, alkyl ether, aryl, substituted alkyl, and substituted aryl. More particularly, R is a radical selected from the group consisting of (C3-C10) alkyl, (C3-C10) allyl, (C3-C10) alkenyl, (C1-C10) haloalkyl, (C2-C10) alkyl ether, (C5-C10) aryl, (C1-C10) substituted alkyl, and (C5-C10) substituted aryl. Exemplary embodiments include Burgess-type reagents wherein R is a radical selected from the group consisting of -CH₂Ph, -CH₂-o-N0₂Ph, -CH₂CH=CH₂, -CH₂CCI₃, and -CH₂CH₂SiMe₃.

Another aspect of the invention is directed to a process for synthesizing cyclic sulfamidates. The process comprises the step of reacting a 1 ,2 diol with an excess of a Burgess reagent or of Burgess-type reagent under reaction conditions for forming the cyclic sulfamidate. In a preferred mode of the process, the 1 ,2 diol is enantiopure and the cyclic sulfamidate is chiral. In another preferred mode of the process, the Burgess-type reagent is represented by the following structure:

In the above structure, -C(0)OR is a carbamate protecting group. Preferred carbamate protecting groups are described above. In an extension of this mode of the invention, the process may further comprise the additional step of deprotecting the cyclic sufamidate for producing a carbamate protected β- aminoalcohol. In turn, this extension may be further extended by then deprotecting the carbamate protected β-aminoalcohol for producing a β- aminoalcohol. Another aspect of the invention is directed to an improved process for synthesizing a product or a product intermediate. The process is of a type that employs a nucleophile selected from the group consisting of 0-, S-, N-, C-, and F-based nucleophiles for converting a cyclic sulfamidate into the product or product intermediate. The improvement comprises the preliminary step of forming the cyclic sulfamidate by reacting a 1 ,2 diol with an excess of a Burgess reagent or a Burgess-type reagent. In a preferred mode, thel ,2 diol is enantiopure and the cyclic sulfamidate is chiral. In another preferred mode, the Burgess-type reagent is represented by the following structure:

° T

In the above structure, -C(0)OR is a carbamate protecting group. Preferred carbamate protecting groups are described above. The nucleophilic conversion of the cyclic sulfamidate is of a type that may be achieved by 0-, S-, N-, C-, and F-based nucleophiles. Exemplary 0-, S-, N-, C-, and F-based nucleophiles include water, sodium azide, sodium cyanide, tefra-n-butyl ammonium fluoride, ammonium thiocyanate, lithium 3-methylbutylamide, pyrazole, piperidine, lithium 4-methoxytoluene α-sulfide, and 4-methoxytoluene α-thiol. Further 0-, S-, N-, C-, and F-based nucleophiles employable for converting the cyclic sulfamidate are disclosed by Lee T. Boulton, et al., in Journal of the Chemical Society, Perkin Transactions 1, 1999, pages 1421-4129.

Another aspect of the invention is directed to a compound represented by the following structure:

This compound is disclosed herein to be useful as in intermediate in the synthesis of diazonamide A.

Brief Description of Drawings:

Figure 1 illustrates the conversion of diols (I) to cyclic sulfamidates (III) using Burgess reagent (1) and proof of principle for (2 → 3).

Figure 2 illustrates a regioselective synthesis of sulfamidates from precursor diols using Burgess reagent (1). [a] As determined by ¹H NMR spectroscopic analysis of the crude reaction products.

Figure 3 illustrates further examples of the regioselective synthesis of sulfamidates from precursor diols using Burgess reagent (1). [a] As determined by ¹H NMR spectroscopic analysis of the crude reaction products.

Figure 4 illustrates an X-Ray crystallographic structure for sulfamidate 29.

Figure 5 illustrates a synthesis of the Burgess reagent and of Burgess-type reagents (39 - 42). Reaction conditions are as follows: a) chlorosulfonyl isocyanate (1.0 equiv), ROH (1.05 equiv), in CH₂CI₂, at 0°C, for 30 min, with a yield of 89-95%; b) Et₃N (2.5 equiv), in C₆H₆, at 25°C, for 1 hour, with a yield of 81-87 %.

Figure 6 illustrates the use of the new Burgess-type reagents 39 - 42 to prepare orthogonally protected sulfamidates (43 - 49). [a] As determined by ¹H NMR spectroscopic analysis of the crude reaction products. Cbz = CO₂CH₂Ph, o-N0₂ = C0₂CH₂-o-N0₂, Alloc = C0₂CH₂CH=CH₂, Troc = C0₂CH₂CCI₃.

Figure 7 illustrates the deprotection of cyclic sulfamidates using aqueous HCI in dioxane at ambient temperature to yield β-aminoalcohols. Detailed Description:

A novel regio- and stereoselective two-stage synthesis of β-aminoalcohols has been achieved in which the key transformation is the creation of a cyclic sulfamidate from a precursor diol, mediated by Burgess-type reagents. The generality and scope of this approach is underscored by the considerable number and variety of substrates which display high levels of selectivity in the process. As such, this method provides facile access to compounds for use in myriad applications, whether as chiral ligands to perform asymmetric synthesis or as molecular probes to explore problems in chemical biology.

Disclosed herein is a two-step process for the regio- and stereoselective synthesis of a wide variety of 1 ,2-aminoalcohols. The process is centered on initial construction of chiral sulfamidates from enantiopure diols, orchestrated by Burgess reagent (1 , Figure 1 ) or Burgess-type reagents, followed by mild treatment with aqueous acid. Also disclosed are several novel Burgess-type reagents which greatly extend the utility of this novel protocol by enabling access to an orthogonal set of Λ/-protected sulfamidates.

It is disclosed herein that a protected variant of a β-aminoalcohol may be generated in the form of a cyclic sulfamidate (III, Figure 1 ) by exposing a diol (I) to excess Burgess reagent (1) (Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744 - 4745; Atkins, G. M.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135 - 6141 ; Burgess, E. M.; et al. J. Org. Chem. 1973, 38, 26 - 31 ). Although the Burgess reagent is typically employed as a powerful dehydrating reagent (for example, effecting the formation of olefins from alcohols) (For reviews on the chemistry of 1 , see: P. Taibe, S. Mobashery in Encyclopedia of Reagents for Organic Synthesis, Vol. 5, L. A. Paquette, Ed.; John Wiley & Sons: Chichester, 1995; pp 3345 - 3347; Burckhardt, S. Synlett 2000, 559), it is shown herein that, after the generation of an intermediate of type II from I, a unique and productive cyclization to sulfamidate III via the proposed S_N2 mechanism can occur in preference to typical pathways involving the loss of water. It is also shown herein that this transformation can then proceed with displacement of the more activated leaving group, and that, variation of the R., and R₂ substituents on enantiopure I enable the stereo- and regioselective synthesis of sulfamidates on diverse structural types.

The synthesis of III disclosed herein represents a more efficient approach than is currently available, since it provides concomitant installation of nitrogen protection. More significantly, since the technology disclosed herein does not rely on the use of β-aminoalcohol starting materials, it provides a unique way to stereoselectively prepare this important functional motif from III simply by using water as a nucleophile.

A proof of principle for this synthetic method was demonstrated as follows. A THF solution of diol 2 (synthesized from the precursor olefin by dihydroxylation under standard conditions) and 2.5 equivalents of Burgess reagent (1) was heated at reflux for one hour. A smooth formation of the desired sulfamidate (3) in 84 % yield was obtained as a single regioisomer based on NMR spectroscopic analysis. Although 1 is available from several commercial sources at prices ranging from US$36 - US$45 per gram, the material is easily synthesized during the course of an afternoon in multigram quantities at a price of less than US$1 per gram following the procedure described in Burgess, E. M.; et al. J. Org. Chem. 1973, 38, 26 - 31. Significantly, because attempted carbamate-based AA (Reddy, K. L; Sharpless, K. B. J. Am. Chem. Soc. 1998, 720, 1207 - 1217; Li, G.; et al. Angew. Chem. 1996, 708, 2995 - 2999; Angew. Chem. Int. Ed. Engl. 1996, 35, 2813 - 2817) on 2 leads to the desired product in modest yield with little control of regioselectivity, while concurrent efforts employing the Ritter reaction under acidic conditions (Bellucci, C. M.; et al. Tetrahedron: Asymmetry 1997, 8, 895 - 902; Senanayake, C. H.; et al. Tetrahedron Lett. 1995, 36, 7615 - 7618; Senanayake, C. H.; et al. Tetrahedron Lett. 1995, 36, 3993 - 3996) leads solely to decomposition, the ease and selectivity of this particular Burgess-mediated transformation teaches a highly useful and applicable synthetic methodology. For alternate, multistep approaches to c/s-1 ,2-aminoalcohols from diols, see: Lakshman, M. K.; Zajc, B. Tetrahedron Lett. 1996, 37, 2529 - 2532; Ghosh, A. K.; et al. Tetrahedron Lett. 1991 , 32, 711 - 714.

With this initial proof of principle achieved, the generality of this reaction process was demonstrated on a selection of styrene-derived diols possessing a broad range of aromatic substitution patterns. The substrates were chosen to demonstrate the role of inductive effects on the regioselectivity of the S_N2-based cyclization. This particular class of compounds was examined not only because it represents the best substrates for Sharpless asymmetric dihydroxylation (AD) in terms of both catalytic activity and enantioselectivity (Kolb, H. C; et al. Chem. Rev. 1994, 94, 2483 - 2547), but also because styrene-type olefins display good but variable yields and regioselection in carbamate-based AA (Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 720, 1207 - 1217; Li, G.; et al. Angew. Chem. 1996, 708, 2995 - 2999; Angew. Chem. Int. Ed. Engl. 1996, 35, 2813 - 2817). As shown in Figure 2, Burgess-mediated sulfamidate synthesis followed the expected pattern for inductive influence in nucleophilic displacement at the benzylic position, as electron-donating groups displayed excellent regioselectivity (entries 1 - 4), while erosion in selectivity relative to simple styrene (entry 5) was observed in those examples bearing electron-withdrawing substituents (entries 6 and 7). In all cases, the products were formed in high yield, and when two regioisomers were formed, the majority were separable by chromatography. Significantly, the poor regioselectivity observed in the conversion of 16 to 17 (entry 7, Figure 2) could be improved to 75:25 by performing the reaction at ambient temperature, albeit at the expense of yield (35 %).

To characterize the role of steric encumbrance on the reaction process, as well as to test the applicability of the reaction process for other structural classes, several additional substrates were employed as indicated in Figure 3. With these additional substrates, it was shown that increasing steric bulk at the terminal position of the styrene core, simply through the addition of a single methyl group (entries 1 and 2), dramatically increased the regioselectivity of cyclic sulfamidate formation compared to the ratios observed for the corresponding examples in Figure 2. Surprisingly, substituents adjacent to the reactive benzylic center on the aromatic ring did not affect either reaction yield or selectivity (entries 3 and 4). Additionally, esters were well-tolerated in the reaction, with near complete regioselection observed for the formation of 29 from 28 (entry 6, Figure 3) due to the mutually reinforcing effects of α-position deactivation by the ester moiety and steric bulk imposed at that site by a methyl group, while competitive steric and electronic effects in entry 7 led to retarded S_N2 displacement at the preferred terminal site, thereby reducing both regioselectivity and yield. Finally, simple aliphatic examples proceeded with extremely high regioselectivity, presumably due to the well-established preference for nucleophilic displacement of primary over secondary leaving groups.

To verify the potential of this reaction for asymmetric synthesis, since all of the examples listed in Tables 1 and 2 were performed on racemic diol substrates, an X-ray crystal structure was obtained for sulfamidate 29 which confirmed that inversion of stereochemistry had occurred at the benzylic position relative to the racemic c/s-diol starting material (see Figure 4). This analysis does not exclude the possibility of inversion at the other center. However, this event is highly unlikely based on mechanistic details elucidated thus far. Additionally, both racemic and enantiopure 26 were synthesized (Enantiopure (R)-26 was prepared using AD-mix-β as described by Becker, H.; et al. J. Org. Chem. 1995, 60, 3940 - 3941 ), and comparison of the chiral HPLC traces of the resultant products (27) indicated that preexisting stereochemical information was communicated in the reaction with complete fidelity (Chiral HPLC analysis was performed using a Diacel^® Chiralpack Column AD, 85 % hexane/15 % isopropanol, 1.5 mL/min, 254 nm, 8.72 min (S-27), 12.2 min (R-27)).

The overall utility of the present sulfamidate synthesis is yet further extended. The synthetic process may be employed to create compounds bearing A/-protection other than a methyl carbamate by modification of 1 , i.e., by the use of Burgess-type reagents. 1 is known to possess both thermal and moistu re-sensitivity (P. Taibe, S. Mobashery in Encyclopedia of Reagents for Organic Synthesis, Vol. 5, L. A. Paquette, Ed.; John Wiley & Sons: Chichester, 1995; pp 3345 - 3347), features which might be modulated by differentiation of the carbamate portion. As delineated in Figure 5, four different Burgess-type reagents (39 - 42), were prepared, representing an orthogonal set of amine protecting groups (based on deprotection by hydrogenation, photolysis, exposure to palladium-based catalysts, or treatment with Zn, respectively) simply by treating chlorosulfonylisocyanate (34) with the alcohol of interest, followed by subsequent exposure to Et₃N. The relative facility of these preparations implies that virtually any carbamate-based Burgess-type salt can be accessed by this approach. Although carbamate-derived Burgess-type salts are quite stable, the corresponding amide-based compounds are unlikely to be readily isolable. For efforts to use such reagents in synthesis, see Burgess, E. M.; et al. J. Org. Chem. 1973, 38, 26 - 31 ; and Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1994, 50, 6549 - 6558. In a demonstration of the effectiveness of these new reagents, exposure of several diol substrates to 39 - 42 resulted in the facile formation of the desired sulfamidate products (43 - 49, Figure 6) in comparable efficiency and selectivity as was observed previously with 1. Significantly, handling of 39 - 42 suggest that they possess unique thermal and moisture-sensitivity profiles relative to 1 , physical features which are significant in effecting transformations typically achieved by Burgess reagent on recalcitrant substrates. Compounds 39 - 42 may also be engaged in transformations already known with 1 , such as oxazole formation from precursor ketoamides (Nicolaou, K. C; et al. Angew. Chem. 2001 , 73, 4841 - 4845; Angew. Chem. Int. Ed. 2001 , 40, 4705 - 4709; Brain, C. T.; Paul, J. M. Synlett 1999, 1642 - 1644).

The transformation of sulfamidate products to β- aminoalcohols is also demonstated herein. This conversion had been previously disclosed in the literature, using a 1/1 mixture of aqueous HCI/dioxane at ambient temperature, only one substrate was examined Baldwin, J. E.; et al. Tetrahedron: Asymmetry 1991 , 7, 881 - 884). As such, it is verify herein that this deprotection protocol has sufficient scope for general synthetic utility. More particularly, several sulfamidates are reacted under these conditions, readily effecting the desired deprotection in each case. A subset of these conversions is provided in Figure 7, with high yields observed in all examples despite relatively large variations in reaction time necessary for complete conversion. The chiral integrity of products resulting from ring opening of the chiral sulfamidate by water under neutral conditions, followed by neutralization with aqueous sodium bicarbonate, has already been verified on a substrate far more prone to undergo racemization (Baldwin, J. E.; et al. Tetrahedron: Asymmetry 1991, 7, 881 - 884).

Experimental Section:

In a representative procedure, the diol (0.5 mmol, 1.0 equiv) was dissolved in anhydrous THF (5 mL) and methoxycarbonylsulfamoyl-triethylammonium hydroxide (1, 0.293 g, 1.25 mmol, 2.5 equiv) was added. The resultant solution was heated at reflux for one hour, cooled to ambient temperature, concentrated, and then filtered through a short plug of silica gel to afford the desired product in high purity.

Although analysis by thin-layer chromatography (TLC) indicates complete consumption of starting materials after a few minutes, non-cyclized material (II, Figure 1 ) remains at the baseline, and heating for additional time is required to effect complete conversion to product (III).

Deprotection of the sulfamidate group was achieved by dissolving the substrate in a 1/1 mixture of dioxane/4 M aqueous HCI and stirring the resultant solution at ambient temperature until complete conversion was observed by TLC. The reaction mixture was then diluted with EtOAc, washed with 5 % aqueous NaHC0₃ and brine, dried over MgS0₄, and concentrated to afford spectroscopically pure product (IV).

Preparation of Buroess-Tvpe Reagents 39 - 42:

To a solution of chlorosulfonylisocyanate (8.71 mL, 100 mmol, 1.0 equiv) in CH₂CI₂ (25 mL) at 0 °C was added a solution of the desired alcohol (1.05 equiv) in CH₂CI₂ (25 mL) dropwise over 30 min. Once the addition was complete, the solvent was concentrated in vacuo, providing the crude desired sulfamoyl chloride (35 - 38). After sufficient drying under vacuum (typically 30 min), a solution of the sulfamoyl chloride (20 mmol, 1.0 equiv) in benzene (40 mL) was added dropwise to a solution of Et₃N (6.27 mL, 45 mmol, 2.25 equiv) in benzene (25 mL) at ambient temperature. After addition was complete (~1 h), the triethylammonium hydrochloride precipitate was removed by filtration, and the filtrate was concentrated in vacuo to afford 39 - 42 as clear oils which eventually solidified.

Physical Data for selected compounds:

3: f?_f = 0.12 (silica gel, ethyl acetate: hexanes 1 :1 ); HR-MS: calcd for C₁₉H₂₁BrN₃0₇S⁺ (M + H⁺): 514.0278, found: 514.0280.

13: R_f = 0.56 (silica gel, ethyl acetate:hexanes 1 :1 ); HR-MS: calcd for

(M + Na⁺): 280.0250, found: 250.0253.

39: ESI-MS for C₁₄H₂₃N₂0₄S⁺ [M + H⁺]: calcd 315, found: 315.

43: R_f = 0.49 (silica gel, ethyl acetate: hexanes 1 :1 ); HR-MS: calcd for C₁₇H₁₇NO₆SNa⁺ (M + H⁺): 386.0669, found: 386.0666.

53: f?_f = 0.61 (silica gel, ethyl acetate: hexanes 1 :1 ); all other data obtained were identical to that reported in Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 720, 1207 - 1217.

Detailed Description of Figures

Figure 1 is a synthetic scheme illustrating the proposed conversion of diols (I) to cyclic sulfamidates (III) using Burgess reagent (1) and proof of principle (2 - 3). Although the Burgess reagent is typically used as a powerful dehydrating agent, it was thought that after the generation of an intermediate of type II from type I, a unique and productive cyclization to sulfamidate III via the proposed S_N2 mechanism could potentially occur in preference to typical pathways involving loss of water. Conversion of 2 to 3 shows that the concept works.

Figure 2 is a synthetic table showing the regioselective synthesis of sulfamidates from precursor diols using Burgess reagent (1). The ratios of regioisomers were determined by ¹H NMR of the crude reaction products. The Burgess-mediated sulfamidate synthesis followed the expected pattern for inductive influence in nucleophilic displacement at the benzylic position, as electron-donating groups displayed excellent regioselectivity (entries 1-4), while erosion in selectivity relative to simple styrene (entry 5) was observed in those examples bearing electron-withdrawing substituents (entries 6 and 7). In all cases, the products formed in high yield, and when two regioisomers were formed, the majority were separable by chromatography.

Figure 3 is a table showing further examples of the regioselective synthesis of sulfamidates from precursor diols using Burgess reagent (1 ). The ratios of regioisomers were determined by ¹H NMR of the crude reaction products. Other structural classes of diols were examined in this table. Increasing steric bulk at the terminal position of the styrene core, simply through the addition of a single methyl group (entries 1 and 2), dramatically increased the regioselectivity of cyclic sulfamidate formation complared to the ratios observed for the corresponding examples in Figure 2. Surprisingly, substituents adjacent to the reactive benzylic center on the aromatic ring did not affect either reaction yield or selectivity (entries 3 and 4). Additionally, esters were well tolerated in the reaction, with near complete regioselection observed for the formation of 29 from 28 (entry 6) due to mutually reinforcing effects of a-position deactivation by the ester moiety and steric bulk imposed at that site by a methyl group. Competitive steric and electronic effects in entry 7 led to retarded S_N2 displacement at the preferred terminal site, thereby reducing both regioselectivity and yield. Finally, simple aliphatic examples proceeded with extremely high regioselectivity, presumably due to the well-established preference for nucleophilic displacement of primary over secondary leaving groups.

Figure 4 shows an X-ray crystallographic structure of sulfamidate 29. This structure confirmed the inversion of stereochemistry at the benzylic center relative to the starting material. Figure 5 shows the synthesis of novel variants of the Burgess reagent. Four different Burgess-type reagents (39 - 42) were prepared, representing an orthogonal set of amine protecting groups (based on deprotection by hydrogenation, photolysis, exposure to palladium-based catalysts, or treatment with Zn, respectively) simply by treating chlorosulfonylisocyanate (34) with the alcohol of interest, followed by subsequent exposure to Et₃N.

Figure 6 shows the use of the new Burgess-type reagents 39 - 42 to prepare orthogonally protected sulfamidates (43-49). The ratios of regioisomers were determined by ¹H NMR of the crude reaction products. Exposure of several diol substrates to 39-42 resulted in the facile formation of the desired sulfamidate products (43-49) in comparable efficiency and selectivity as observed previously with 1.

Figure 7 is a table showing the deprotection of the cyclic sulfamidates using aqueous Hcl in dioxane at ambient temperature to yield b-aminoalcohols. High yields were observed in all examples despite the relatively large variations in reaction time necessary for complete conversion. The chiral integrity of the products resulting from ring opening of the chiral sulfamidate by water under neutral conditions, followed by neutralization with aqueous sodium bicarbonate, has already been verified on a substrate far more prone to undergo racemization (Baldwin, J. E.; et al. Tetrahedron: Asymmetry 1991 , 7, 881-884).

Claims

What is claimed is:

1. A Burgess-type reagent represented by the following structure:

θ Θ

Et₃N-S-N .OR

O " Y O

wherein -C(0)OR is a carbamate protecting group, with a proviso that R is not methyl, ethyl, or polyethylene glycol.

2. A Burgess-type reagent according to claim 1 wherein R is a radical selected from the group consisting of alkyl, allyl, alkenyl, haloalkyl, alkyl ether, aryl, substituted alkyl, and substituted aryl.

3. A Burgess-type reagent according to claim 1 wherein R is a radical selected from the group consisting of (C3-C10) alkyl, (C3-C10) allyl, (C3-C10) alkenyl, (C1- C10) haloalkyl, (C2-C10) alkyl ether, (C5-C10) aryl, (C1-C10) substituted alkyl, and (C5-C10) substituted aryl.

4. A Burgess-type reagent according to claim 1 wherein R is a radical selected from the group consisting of -CH₂Ph, -CH₂-o-N0₂Ph, -CH₂CH=CH₂, -CH₂CCI₃, and -CH₂CH₂SiMe₃.

5. A process comprising the following step:

reacting a 1 ,2 diol with an excess of a Burgess reagent or a Burgess-type reagent under reaction conditions for forming a cyclic sulfamidate.

6. A process according to claim 5 wherein the 1 ,2 diol is enantiopure and the cyclic sulfamidate is chiral.

7. A process according to claim 5 wherein the Burgess-type reagent is represented by the following structure:

wherein -C(0)OR is a carbamate protecting group.

8. A process according to claim 7 wherein R is a radical selected from the group consisting of alkyl, allyl, alkenyl, haloalkyl, alkyl ether, aryl, substituted alkyl, and substituted aryl.

9. A process according to claim 7 wherein R is a radical selected from the group consisting of (C2-C10) alkyl, (C3-C10) allyl, (C3-C10) alkenyl, (C1-C10) haloalkyl, (C2-C10) alkyl ether, (C5-C10) aryl, (C1-C10) substituted alkyl, and (C5-C10) substituted aryl.

10. A process according to claim 5 further comprising the following additional step:

deprotecting the cyclic sufamidate for producing a carbamate protected β- aminoalcohol.

11. A process according to claim 10 further comprising the additional following step:

deprotecting the carbamate protected β-aminoalcohol for producing a β- aminoalcohol.

12. In an improved process for synthesizing a product or a product intermediate, the process being of a type employing a nucleophile selected from the group consisting of 0-, S-, N-, C-, and F-based nucleophiles for converting a cyclic sulfamidate into the product or product intermediate, the improvement comprising the following preliminary step:

forming the cyclic sulfamidate by reacting a 1 ,2 diol with an excess of a Burgess reagent or a Burgess-type reagent.

13. A process according to claim 12 wherein the 1 ,2 diol is enantiopure and the cyclic sulfamidate is chiral.

14. A process according to claim 12 wherein the Burgess-type reagent is represented by the following structure:

© Θ

Et₃N-S-NL .OR

6 Y

wherein -C(0)OR is a carbamate protecting group.

15. A process according to claim 12 wherein R is a radical selected from the group consisting of alkyl, allyl, alkenyl, haloalkyl, alkyl ether, aryl, substituted alkyl, and substituted aryl.

16. A process according to claim 15 wherein R is a radical selected from the group consisting of (C2-C10) alkyl, (C3-C10) allyl, (C3-C10) alkenyl, (C1-C10) haloalkyl, (C2-C10) alkyl ether, (C5-C10) aryl, (C1-C10) substituted alkyl, and (C5-C10) substituted aryl.

17. A process according to claim 16 wherein R is a radical selected from the group consisting of -CH₂Ph, -CH₂-o-N0₂Ph, -CH₂CH=CH₂, -CH₂CCI₃, and - CH₂CH₂SiMe₃.

18. A compound represented by the following structure: