Site-selective catalysis of phenyl thionoformate transfer as a tool for regioselective deoxygenation of polyols

Article abstract of DOI:10.1021/jo702334z

(Chemical Equation Presented) We report the application of peptide-embedded imidazoles as catalysts for the site-selective delivery of the phenyl thionoformate unit as a prelude to deoxygenation reactions of polyols. Methodology was developed that allows for the synthesis of thiocarbonyl derivatives based on a combination of additives that include N-alkylimidazoles and FeCl₃ as co-catalysts. The use of this reagent combination leads to increased reaction rates and efficient yields relative to those of simple base-mediated reactions. In terms of controlling regioselectivity during the course of polyol modification, we found that histidine-containing peptides, in combination with FeCl₃, could lead to modulation of the product distribution. Through screening of peptides and control of reaction conditions, products could be observed that reflected both the inherent preference of substrates and also reversal of inherent selectivity.

Full text of DOI:10.1021/jo702334z

Site-Selective Catalysis of Phenyl Thionoformate Transfer as a Tool
for Regioselective Deoxygenation of Polyols
Mar´ıa Sa´nchez-Rosello´,† Angela L. A. Puchlopek,† Adam J. Morgan,‡ and
Scott J. Miller*,†,‡
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107, and
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
scott.miller@yale.edu
ReceiVed October 29, 2007
We report the application of peptide-embedded imidazoles as catalysts for the site-selective delivery of
the phenyl thionoformate unit as a prelude to deoxygenation reactions of polyols. Methodology was
developed that allows for the synthesis of thiocarbonyl derivatives based on a combination of additives
that include N-alkylimidazoles and FeCl3 as co-catalysts. The use of this reagent combination leads to
increased reaction rates and efficient yields relative to those of simple base-mediated reactions. In terms
of controlling regioselectivity during the course of polyol modification, we found that histidine-containing
peptides, in combination with FeCl3, could lead to modulation of the product distribution. Through
screening of peptides and control of reaction conditions, products could be observed that reflected both
the inherent preference of substrates and also reversal of inherent selectivity.
Introduction
McCombie reaction.3 Any successful approach to this problem
requires catalysts that are particularly effective for mediating
regioselective reactions, a current challenge in stereoselective
synthesis.4
Our overall strategy was to employ the emerging paradigm
of asymmetric nucleophilic catalysis5 for the projected group
transfer reactions. While this field has exploded with a myriad
of exciting catalyst types, including DMAP analogs,6 phos-
phines,7 amidines,8 and other nucleophilic functional groups,9
The deoxygenation of alcohols is a fundamental transforma-
tion in organic synthesis.1 The development of catalysts that
could selectively remove a hydroxyl group from a polyol
structure would be a particularly advantageous method in
medicinal chemistry settings because one might use the tech-
nique to obtain deoxyanalogs of polyol agents without elaborate
syntheses or complicated protecting group schemes (Scheme
1).2 To develop such methodology, we began an investigation
of site-selective transfer of the thiocarbonyl group as a prelude
to substrate deoxygenation, utilizing the venerable Barton-
(2) (a) Graham, A. E.; Thomas, A. V.; Yang, R. J. Org. Chem. 2000,
65, 2583-2585. (b) Morgan, A. J.; Wang, Y. K.; Roberts, M. F.; Miller, S.
J. J. Am. Chem. Soc. 2004, 126, 15370-15371. (c) Go´mez, A. M.; Moreno,
E.; Valverde, S.; Lo´pez, J. C. Eur. J. Org. Chem. 2004, 1830-1840. (d)
Wang, Y. K.; Morgan, A. J.; Stieglitz, K.; Stec, B.; Thompson, B.; Miller,
S. J.; Roberts, M. F. Biochemistry 2006, 45, 3307-3314.
(3) (a) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574-1585. (b) Barton, D. H. R.; Blundell, P.; Dorchak, J.; Jang,
D. O.; Jaszberenyi, J. Cs. Tetrahedron 1991, 47, 8969-8984. (c) Barton,
D. H. R.; Dorchak, J.; Jaszberenyi, J. Cs. Tetrahedron 1992, 48, 7435-
7446.
† Yale University.
‡ Boston College.
(1) (a) Hartwig, W. Tetrahedron 1983, 39, 2609-2645. (b) Crich, D.;
Quintero, L. Chem. ReV. 1989, 89, 1413-1432. (c) Lopez, R. M.; Hays,
D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949-6950. (d) Yasuda,
M.; Onisi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66, 7741-
7744. (e) Schlaf, M.; Ghosh, P.; Fagan, P. J.; Hauptman, E.; Bullock, R.
M. Angew. Chem., Int. Ed. 2001, 40, 3887-3890.
10.1021/jo702334z CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/30/2008
1774
J. Org. Chem. 2008, 73, 1774-1782

Site-SelectiVe Catalysis of Phenyl Thionoformate Transfer
SCHEME 1
SCHEME 2
we sought to capitalize on developments in our own laboratory
around peptide-embedded nucleophiles (e.g., 1).10 In this spirit,
we have demonstrated that short peptide derivatives of histidine
allow for highly enantioselective and site-selective alcohol
derivatizations,11 among them acylations (i.e., to deliver 2),12
phosphorylations (3),13 and transfer of sulfur-based electrophiles
(4) (Scheme 2).14,15
The portability of the catalysis strategy to thiocarbonyl
transfer is not straightforward. Although the literature contains
numerous examples of thiocarbonylation as a prelude to
deoxygenation,16 the details of catalytic protocols are often
SCHEME 3
(4) (a) Kurahashi, T.; Mizutani, T.; Yoshida, J. J. Chem. Soc., Perkin
Trans. 1 1999, 465-473. (b) Gani, D. Nature 2001, 414, 703-705. (c)
Kurahashi, T.; Mizutani, T.; Yoshida, J. Tetrahedron 2002, 58, 8669-8677.
(d) Hu, G.; Vasella, A. HelV. Chim. Acta 2002, 85, 4369-4391. (e) Kattnig,
E.; Albert, M. Org. Lett. 2004, 6, 945-948. (f) Moitessier, N.; Englebienne,
P.; Chapleur, Y. Tetrahedron 2005, 61, 6839-6853. (g) Wang, C.-C.; Lee,
J.-C.; Luo, S.-Y.; Kulkarni, S. S.; Huang, Y.-W.; Lee, C.-C.; Chang, K.-
L.; Hung, S.-C. Nature 2007, 446, 896-899.
(5) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420. (b) Vedejs, E.;
Daugulis, O., MacKay, J. A.; Rozners, E. Synlett 2001, 1499-1505. (c)
France, S.; Guerin, D. J.: Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103,
2985-3012. (d) Denmark, S. E.; Fu, J. Chem. Commun. 2003, 167-170.
(e) Spivey, A. C.; Arseniyadis, S.; Fekner, T.; Maddaford, A.; Leese, D. P.
Tetrahedron 2006, 62, 295-301.
(6) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809-1810.
(b) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997,
119, 3169-3170. (c) Arai, S.; Bellemin-Laponnaz, S.; Fu, G. C. Angew.
Chem., Int. Ed. 2001, 40, 234-236. (d) Shaw, S. A.; Aleman, P.; Vedejs,
E. J. Am. Chem. Soc. 2003, 125, 13368-13369. (e) Spivey, A. C.; Zhu, F.;
Mitchell, M. B.; Davey, S. G.; Jarvest, L. R. J. Org. Chem. 2003, 68, 7379-
7385. (f) Fu, G. C. Acc. Chem. Res. 2004, 37, 542-547. (g) Spivey, A. C.;
Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436-5441.
(7) (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488-
9489. (b) Vedejs, E.; Daugulis, O.; Harper, L. A.; MacKay, J. A.; Powell,
D. R. J. Org. Chem. 2003, 68, 5020-5027. (c) Methot, J. L.; Roush, W. R.
AdV. Synth. Catal. 2004, 346, 1035-1050 and references therein.
(8) (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J.
J. Am. Chem. Soc. 2004, 126, 12226-12227. (b) Birman, V. B.; Jiang, H.
Org. Lett. 2005, 7, 3445-3447. (c) Birman, V. B.; Li, X.; Jiang, H.; Uffman,
E. W. Tetrahedron 2006, 62, 285-294. (d) Birman, V. B.; Li, X.; Han, Z.
Org. Lett. 2007, 9, 37-40.
variable. There are cases in which nucleophilic catalysts such
as DMAP are employed,17 but often pyridine is used simulta-
neously;18 there are also reports where thiocarbonylation is
carried out at high temperature in the absence of a catalyst.19
Nonetheless, we began our studies with the goal of exploring
whether the catalytic cycle described in Scheme 3 might be
viable. Our plan was to examine the potential of catalysts like
1 to capture phenyl chlorothionoformate (5) with the expectation
that intermediates related to 6 would be formed. Transfer of
thiocarbonyl to substrate would then deliver product 7, while
regenerating catalyst 1. Described below are our findings in
connection to our exploration of this potential catalytic cycle.
(9) Chiral diamines: (a) Oriyama, T.; Imai, K.; Hosoya, T.; Sano, T.
Tetrahedron Lett. 1998, 39, 397-400. (b) Oriyama, T.; Imai, K.; Sano, T.;
Hosoya, T. Tetrahedron Lett. 1998, 39, 3529-3532. Nucleophilic car-
benes: Enders, D.; Balensiefer, B. Acc. Chem. Res. 2004, 37, 534-541.
(10) Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610.
(14) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A. J. Am.
Chem. Soc. 2004, 126, 8134-8135.
(15) For a related approach involving alcohol silylation, see: (a) Isobe,
T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun. 2001, 243-244.
(b) Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006,
443, 67-70.
(16) Barton, D. H. R.; Ferreira, J. A.; Jaszberenyi, J. C. PreparatiVe
Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York,
1997; pp 151-172.
(17) Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J. Org. Chem.
1990, 55, 5181-5183.
(11) (a) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869-
8875. (b) Lewis, C. A.; Miller, S. J. Angew. Chem., Int. Ed. 2006, 45, 5616-
5619.
(12) (a) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus, P.
J., Jr.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643. (b)
Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496-6502.
(c) Fierman, M. B.; O’ Leary, D. J.; Steinmetz, W. E.; Miller, S. J. J. Am.
Chem. Soc. 2004, 126, 6967-6971. (d) Lewis, C. A.; Chiu, A.; Kubryk,
M.; Balsells, J.; Pollard, D.; Esser, C. K.; Murry, J.; Reamer, R. A.; Hansen,
K. B.; Miller, S. J. J. Am. Chem. Soc. 2006, 128, 16454-16455.
(13) (a) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
10125-10126. (b) Sculimbrene, B. R.; Morgan, A. J.; Miller, S. J. J. Am.
Chem. Soc. 2002, 124, 11653-11656. (c) Sculimbrene, B. R.; Morgan, A.
J.; Miller, S. J. Chem. Commun. 2003, 1781-1785. (d) Sculimbrene, B.
R.; Xu, Y.; Miller, S. J. J. Am. Chem. Soc. 2004, 126, 13182-13183.
(18) For three examples of syntheses where both DMAP and pyridine
are used in combination to effect thiocarbonylation, see: (a) Denmark, S.
E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672-5680. (b) Rigby, J. H.;
Mateo, M. E. Tetrahedron 1996, 52, 10569-10582. (c) Shimokawa, J.;
Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int.
Ed. 2004, 43, 1559-1562.
(19) Gaudino, J. J.; Wilcox, C. S. J. Am. Chem. Soc. 1990, 112, 4374-
4380.
J. Org. Chem, Vol. 73, No. 5, 2008 1775

Sa´nchez-Rosello´ et al.
TABLE 1. Thiocarbonylation Reaction of 2,4,6-Tribenzyl myo-Inositol
Results and Discussion
we sought to identify conditions that would employ a base (to
scavenge the full equivalent of HCl generated in these reactions)
that was not itself a promoter of the reaction. During the course
of these studies, we found an intriguing difference in reactivity
between simple substrates such as cyclohexanol and oxygenated
substrates such as carbohydrate derivatives like inositide 10,22
glucosamine derivative 11,23 and glucose derivative 12a.24
Preliminary Experiments. To clarify the basics of catalytic
thiocarbonyl transfer, we carried out several simple experiments
that show that neither DMAP nor NMI is generally effective as
a substoichiometric catalyst for the thiocarbonylation of simple
substrates to give 8 from cyclohexanol. Notably, as shown in
eq 1, when reactions are conducted with DMAP in the presence
of Et3N, thiocarbonate 8 is not formed. Rather, the addition
product 9, derived from triethylamine addition to phenyl
chlorothionoformate followed by dealkylation, is formed prefer-
ably as the major product (eq 1).20 On the other hand,
thiocarbonate 8 is readily obtained when the reaction is
performed with a variety of pyridines, suggesting that a general
base mechanism may result in efficient reactions at room
temperature (eq 2).
As shown in Table 1, with myo-inositol derivative 10 as a
substrate, we observed generally slower base-promoted thio-
carbonylation reactions. Thus, as shown in entry 1, use of
pyridine as a promoter allowed observation of (()-13 in only
20% conversion, as measured by 1H NMR. Inclusion of DMAP
(20 mol %) in the reaction mixture led to essentially identical
results (entry 2), whereas the combination of 2,6-lutidine with
DMAP actually led to no reaction (entry 3). On the other hand,
(20) (a) Hsu, F. L.; Zhang, X.; Hong, S. S.; Berg, F. J.; Miller, D. D.
Heterocycles 1994, 39, 801-809. (b) Millan, D. S.; Prager, R. H. Aust. J.
Chem. 1999, 841-849.
(21) (a) Guibe-Jampel, E.; Bram, G.; Vilkas, M. Bull. Soc. Chim. Fr.
1973, 1021-1027. (b) Pandit, N. K.; Connors, K. A. J. Pharm. Sci. 1982,
71, 485-491. (c) Breslow, R. J. Mol. Catal. 1994, 91, 161-174.
(22) (a) Lee, H. W.; Kishi, Y. J. Org. Chem. 1985, 50, 4402-4404. (b)
Billington, D. C.; Baker, R.; Kulagowski, J. J.; Mawer, I. M.; Vacca, J. P.;
Jane deSolms, S.; Huff, J. R. J. Chem. Soc., Perkin Trans. 1989, 1, 1423-
1429.
(23) RajanBabu, T. V.; Ayers, T. A.; Halliday, G. A.; You, K. K.;
Calabrese, J. C. J. Org. Chem. 1997, 62, 6012-6028.
(24) Ferro, V.; Mocerino, M.; Stick, R. V.; Tilbrook, D. M. G. Aust. J.
Chem. 1988, 41, 813-815.
To explore a possible catalytic reaction in which an N-
alkylimidazole might function by a nucleophilic mechanism,21
1776 J. Org. Chem., Vol. 73, No. 5, 2008

Site-SelectiVe Catalysis of Phenyl Thionoformate Transfer
CHART 1. Substrates for Which No Reaction Was
Observed within 24 h under the Catalytic Conditions
robust catalytic conditions were identified when 1,2,2,6,6-
pentamethylpiperidine (PEMP) was employed as a base in
combination with NMI as a catalyst. PEMP alone was found to
afford no background rate under the conditions we explored
(entry 4); use of PEMP in combination with 20 mol % NMI,
on the other hand, led to 90% conversion to (()-13 within 18
h (entry 5); a combination of PEMP and 20 mol % DMAP led
to a slightly less efficient reaction (76% conversion; entry 6).
As shown in entries 7-10, PEMP was found to be superior to
a range of other bases in combination with NMI as a catalyst.
The thionoformate was also varied (entries 11-13), which leads
to comparable results.
Identification of an FeCl3 Effect. To address the lack of
generality of the PEMP/NMI conditions, we began to explore
additives that might accelerate the reactions of recalcitrant
substrates. Among the hypotheses we explored was the idea
that phenyl chlorothionoformate could be activated through the
use of a co-catalytic amount of a Lewis acid. Indeed, we found
that incorporation of a substoichiometic amount of FeCl3 (15
mol %) led to a dramatic increase in the rate of the reactions in
the presence of PEMP (2 equiv) and NMI (20 mol %). Whereas
no reaction was observed with cyclohexanol in the presence of
phenyl chlorothionoformate and PEMP/NMI (Scheme 4, Reac-
tion A), rapid consumption of cyclohexanol was observed when
FeCl3 (15 mol %) was introduced (Scheme 4, Reaction B). In
terms of control experiments, no reaction was observed in the
corresponding reaction when cyclohexanol was exposed to
phenyl chlorothionoformate, PEMP, and FeCl3 in the absence
of catalytic NMI (Scheme 4, Reaction C). Of further note, in
the rapid reaction containing each of the catalytic additives,
monoaddition product 8 is not the sole significant product. In
With seemingly robust conditions identified for NMI-
catalyzed thionoformate transfer in hand (Table 1, entry 5; eq
3), we sought to examine the scope for a wide variety of
substrates. Surprisingly, as shown in Chart 1, the conditions
were strikingly specific for carbohydrate derivatives. Examina-
tion of seven “simple” substrates revealed that compounds such
as cyclohexanol and 14-19 underwent no reaction under the
identical conditions that led to efficient formation of (()-13.
Indeed, inositol derivative (()-13 could be obtained in 78%
isolated yield within 1 h of reaction time under the preparative,
catalytic conditions (eq 4). Glucosamine derivative 11 is
efficiently converted to a 4:1 mixture of the corresponding
mono- and bis(thionoformates) 20 and 21 in 69% combined
yield (eq 5). Glucose derivative 12a is converted to an 82%
combined, isolated yield of thionoformates 22a, 23a, and 24a
within 1 h under the identical conditions (eq 6).
SCHEME 4
J. Org. Chem, Vol. 73, No. 5, 2008 1777

Sa´nchez-Rosello´ et al.
fact, over-addition product 25 is also observed (70% combined
yield), with compound 8 and 25 being formed in a 1:1 ratio.
However, the amount of the over-addition product may be
decreased by using a larger excess of phenyl chlorothionofor-
mate, as is exemplified in eq 7. Similar results were obtained
with cyclooctanol, whereas other “simple” alcohols such as 15
and 16 turned out to be less reactive, requiring 50 mol % FeCl3
and refluxing dichloromethane for 5 h to give the desired
thiocarbonylation products.
FIGURE 1. Some potential modes of FeCl3 activation of thiono-
formylation reactions.
CHART 2. Catalysts Employed in the Thiocarbonylation
Reaction
At this stage, it is too preliminary to state definitively what
the role of the FeCl3 co-catalyst is for these more rapid
thionoformylation reactions. Among the potential roles we have
considered are (a) that FeCl3 activates phenyl chlorothionofor-
mate in analogy to its role in Friedel-Crafts chemistry (e.g.,
Figure 1, complex A or complex B);25 (b) that NMI-FeCl3
complexes are formed that in turn activate the reagent (e.g.,
Figure 1, complex C); (c) that substrate-metal alkoxides are
formed that perturb reactivity (e.g., Figure 1, complex D).26
These mechanistic possibilities are not easily resolved and will
be the subject of future studies in our laboratory.
Case Studies in Regioselective Polyol Thiocarbonylation
and Deoxygenation. Given the role of deoxysugars in numerous
natural products,27 we chose several simple carbohydrate
derivatives as a testing ground for the application of these
catalytic thiocarbonylation conditions to site-selective deoxy-
genations. Our studies began with an examination of R-methyl
glucoside 12a (eq 8), and the goal of identifying two sets of
catalytic conditions: one that would favor the formation of the
mono-functionalized 2-thiocarbonate 22a and an orthogonal
catalytic reaction that would favor the regioisomer, 3-thiocar-
bonate 23a. Of course, we were keenly aware of the possibility
of overfunctionalization to give bis(thiocarbonate) 24a and also
the possible formation of cyclic thiocarbonate 26a.
Any study of regiochemical functionalization also requires a
set of minimal control experiments that document (a) the
inherent preferences in the hierarchical reactivity within the
substrate and (b) the potential for thermodynamic equilibration
of products such as 22a-24a and 26a under the reaction
conditions. In the studies we describe below, each case includes
a delineation of a hierarchical reactivity of the regiotopic
hydroxyl groups in the presence of a given set of reaction
conditions. Typically, these involve the use of NMI and FeCl3,
each in substoichiometric quantity, in the presence of a
stoichiometric quantity of PEMP. Subsequently, we present the
perturbation of the inherent product distribution (defined by the
outcome with NMI/FeCl3-PEMP), to give different product
ratios as a function of the NMI-embedded peptide structure
(e.g., 27 versus 28; Chart 2). In the following cases, isolation
of the pure mono(thiocarbonates) and resubmission to the
reaction conditions revealed them to be non-interconverting
under the reaction conditions. As a result, the data presented
seem to reflect kinetic selectivities for the site-selective
derivatizations we studied. Gratifyingly, in each of the cases
we examined, we were able to identify catalyst-dependent
reversals of inherent site-selectivity, a manifestation of the
ability of these reaction conditions to exhibit kinetic selectiv-
ity.
Thus, our investigation of regioselective thiocarbonylation
of 12a began with a documentation of the “inherent” regiose-
lectivity under the optimized conditions and under conditions
of various control experiments. As shown in Table 2, entries 1
and 2, the inherent NMI-catalyzed ratio of products appears to
1
be ∼2:1, either when the reaction is monitored by H NMR
(entry 1) or when ratios are assessed by quantitative product
isolation by careful silica gel chromatography (entry 2). As in
our earlier studies, FeCl3 alone does not promote the reaction
(entry 3). The inherent selectivity under the NMI/FeCl3 condi-
tions is somewhat different. As illustrated in entries 4 and 5,
(25) Diaz, D. D.; Miranda, P. O.; Padron, J. I.; Martin, V. S. Curr. Org.
Chem. 2006, 10, 457-476.
(26) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.
(27) See ref 2.
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Site-SelectiVe Catalysis of Phenyl Thionoformate Transfer
a
TABLE 2. Regioselectivity in the Thiocarbonylation of 4,6-Benzylidene r-Methyl Glucoside (eq 8)
a All reactions were conducted in the presence of PEMP ( 2 equiv) and run according to the standard conditions described in Experimental Section.
b Conversion determined by 1H NMR. c Isolated yield after flash chromatography. d The reaction was conducted at -40 °C, 5 h. e The reaction was conducted
at -25 °C, 5 h.
under these conditions 22a and 23a appear in essentially a 1:1
ratio. In each of the reactions containing NMI, a substantial
amount of the over-addition product 24a is also observed.
Nonetheless, the equivalence in reactivity of the 2- and
3-positions of 12a under these conditions sets the stage for
diverting the product distribution in either direction, as a function
of the NMI-embedded peptide structure.28 Our choice of peptides
for screening derives from our historical catalyst libraries that
we have amassed over several years of study. In particular,
catalyst libraries have been assembled from both designed
libraries and random libraries that we prepared for various
projects involving alcohol derivatization.29 Notably, catalyst 27
contributes to an enhancement of the 2-substituted product 22a,
whether FeCl3 is excluded as a co-catalyst (22a:23a ) 11.7:1,
entry 6) or whether it is included (7.6:1, entry 7). Furthermore,
when this reaction is conducted at -40 °C, the 2-substituted
product 22a is formed in a 22:1 ratio, and may be isolated in
67% yield (entry 8).
We note parenthetically that each of the compounds pre-
pared with the site-selective thiocarbonylations is readily
converted to the deoxygenated species using a common set
of standard Barton-McCombie reaction conditions. Thus,
deoxysugars 29-31 are readily obtained by this method (eqs
9-11).
A peptide-dependent reVersal in regioselectivity was observed
when peptide 28 was used as a co-catalyst in place of 27.
Interestingly, the reversal was only observed when the peptide-
FeCl3 co-catalyst combination was employed. When catalyst
28 is used exclusively, a 22a:23a ratio of 1.7:1 is observed (entry
9). In the presence of FeCl3, however, the ratio reverses to 1:4
(entry 10) and is amplified to 1:6.6 when the reaction is
conducted at low temperature, enabling isolation of 23a in 53%
yield under these conditions (entry 11). These results represented
an encouraging illustration of the possibility of controlling the
regiochemical outcome of these thiocarbonylations as a function
of the specific catalytic conditions. Moreover, contrasting entries
7 and 11 illustrates the potential for different regioselectivity
outcomes that are fully attributable to the chiral, functionality-
rich environment provided by the peptide structure.
In an effort to establish the generality of this first-generation
set of conditions, we explored several other simple derivatives
of glucose. Thus, the thiocarbonylation on the R-isopropyl
glucoside 12b gave essentially the same product distribution
as the corresponding R-methyl derivative 12a: peptide 27
enhanced the reactivity for the 2 position to give 22b prefer-
entially, whereas peptide 28, in combination with FeCl3, reversed
the product distribution to favor the 3-thiocarbonyl derivative
23b (eq 12).
(28) After screening about 100 peptides of different length and structure,
we found pentapeptide 27 and octapeptide 28 showed the most regiodi-
vergent behavior in the thiocarbonylation of R-methyl glucoside 12.
(29) A representative comparison of such libraries may be found in the
following article: Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J.
J. Org. Chem. 2001, 66, 5522-5527.
Clearly, in the absence of a detailed role of the peptide
structure in translating stereochemical information to the
substrate, screening of diverse peptide catalyst libraries is one
J. Org. Chem, Vol. 73, No. 5, 2008 1779

Sa´nchez-Rosello´ et al.
overall with â-glucoside 32 are small. It is possible that a more
comprehensive screen of peptide co-catalysts could provide a
more dramatic result. In the context of the present study, it may
suffice to say that the differentiation of â-glucosides of glucose,
with the 4-position protected, may provide
a partic-
ular challenge to regioselective catalysis in this “all-equatorial”
array.
Finally, we decided to investigate the reactivity in a more
complex setting. To compare with the glucose derivatives
previously studied, we synthesized the 4,6-O-benzylidene-1′,6′-
bis-O-tert-butyldiphenylsilyl protected sucrose derivative 37
(eq 14).30 As shown in Table 4, with NMI as catalyst, the 3′-
position is slightly more reactive than the 2-position on the
hexose ring (entry 1). Notably, the 3-position of the glucose
ring is substantially less reactive still. A brief screen of peptide
catalysts and conditions revealed that the potential exists for
modulating the site-selectivity of these thiocarbonylations.
For example, when peptide 27 is employed as a catalyst,
modest 2:1 preference for reaction of the 2-position of the
glucoside is favored to deliver 38 as the major product
(entry 2). In contrast, peptide 28 reverses the site-selectiv-
ity to the 3-position of the fructoside to favor 39 in a ratio of
1:2 (entry 3). While the reversal is modest in these cases, we
suspect that a more extensive screening of catalysts and
conditions could lead to more dramatic reversals in terms of
magnitude.
way forward in finding analogous reversals of kinetic regiose-
lectivity. One such study of interest includes the simple â-methyl
glucoside 32, which provides a direct comparison to our study
of R-anomer 12a. As shown in eq 13, the issues are similar in
terms of the potential for a complex product distribution, with
derivatives 33-36 possible. With the â-anomer, the inherent
product distribution for the formation of 2- versus 3-mono-
(thiocarbonates) (i.e., 33:34) is 1:2 under catalysis by NMI in
the absence of FeCl3, and a similar ratio (1:1.6) is observed in
the presence of both NMI and FeCl3 (Table 3, entries 1 and 2).
In this case, our “hit” peptides for the R-glucoside were less
successful in terms of regioselectivity. Entry 3 shows that
peptide catalyst 27, in the absence of FeCl3, provides a modest
preference for 3-thiocarbonate 34 (1:1.5). Alternatively, peptide
28 provides a modest preference for 2-thiocarbonate 33 (1.5:1;
entry 5). In both cases, the inclusion of FeCl3 in the reaction
mixture provides subtle modulation of ratios, but the effects
Notably, sucrose derivatives 38 and 39 were readily deoxy-
genated to give deoxy-sucrose derivatives 40 and 41 (eqs 15
and 16). Such sequences may provide straightforward access
to deoxygenated disaccharide derivatives with enhanced ef-
ficiencies in comparison to the corresponding reactions wherein
a single catalyst is employed to obtain a given product
distribution.
TABLE 3. Regioselectivity in the Thiocarbonylation of 4,6-Benzylidene â-Methyl Glucosidea,b
a All reactions were conducted in the presence of PEMP and run according to the standard conditions described in Experimental Section.
27: BOC-Pmh-DPro-Aib-DTrp(Boc)-DPhe-OMe. 28: BOC-Pmh-Thr(tBu)-DVal-His(trt)-DPhe-DVal-Thr(tBu)-Ile-OMe. b Conversion determined by 1H
NMR.
1780 J. Org. Chem., Vol. 73, No. 5, 2008

Site-SelectiVe Catalysis of Phenyl Thionoformate Transfer
TABLE 4. Regioselectivity in the Thiocarbonylation of Sucrose
Derivative 37a
rather than substrate control only could be utilized to deliver
alternative major products in the polyol settings. Such reactions
hold the potential to reduce the chemist’s dependence on
protecting groups by designing direct thiocarbonylation-deoxy-
genation sequences that may be of interest in synthetic and
medicinal chemistry applications.
The mechanistic basis of these reversals is a frontier activity
in the developing area of asymmetric catalysts that modulate
regioselectivity. We have taken important first steps in our
studies of chiral, peptide-based asymmetric catalysts.31 That
these new protocols include a significant, metal-based co-catalyst
increases the complexity of these catalytic reactions in signifi-
cant ways. The elucidation of how peptide-based systems
function in the presence of additives like FeCl3 is an exciting
challenge that we are now addressing in our laboratory.
Experimental Section
General Procedures for the Thiocarbonylation Reaction.
General Procedure A. Phenyl chlorothionoformate (1.5 equiv),
1,2,2,6,6-pentamethyl piperidine (2.0 equiv), and N-methylimidazole
or a peptide catalyst (0.20 equiv) were added sequentially to a
flame-dried 10-mL round-bottom flask containing a solution of
alcohol, diol, or polyol (1.0 equiv) in anhydrous dichloromethane
(1 mL). The reaction (yellow or brown) solution was stirred at room
temperature for 1 h, then quenched with 1 mL of methanol, and
concentrated under reduced pressure. The mixture of reaction
products was isolated by silica gel flash chromatography.
General Procedure B. Phenyl chlorothionoformate (1.5 equiv),
1,2,2,6,6-pentamethyl piperidine (2.0 equiv), N-methylimidazole
or a peptide catalyst (0.20 equiv), and FeCl3 (0.15 equiv) were
added sequentially to a flame-dried 10-mL round-bottom flask
containing a solution of alcohol, diol, or polyol (1.0 equiv) in
anhydrous dichloromethane (1 mL). The reaction (yellow or brown)
mixture was stirred at room temperature for 1 h, then quenched
with 1 mL of methanol, and concentrated under reduced pressure.
The mixture of reaction products was isolated by silica gel flash
chromatography.
a All reactions were conducted in the presence of PEMP and run accord-
ing to the standard conditions described in the Experimental Section. 27:
BOC-Pmh-DPro-Aib-DTrp(Boc)-DPhe-OMe. 28: BOC-Pmh-Thr(t-Bu)-
DVal-His(trt)-DPhe-DVal-Thr(t-Bu)-Ile-OMe. b Isolated yield after flash
chromatography.
NOTE: Optimized reaction conditions are described for each
respective substrate. Unless otherwise noted, reactions were run
according to conditions (General Procedure A or B) described
above.
4, 6-O-Benzylidene 2-Mono(thiocarbonate) R-Methyl Gluco-
side 22a. General Procedure A for thiocarbonylation was followed;
glucose derivative 12a (40 mg, 0.14 mmol) was employed as
starting material with peptide 27 (25 mg, 0.028 mmol), phenyl
chlorothionoformate (28 µL, 0.21 mmol), and 1,2,2,6,6-pentamethyl
piperidine (51 µL, 0.28 mmol) in CH2Cl2 (1.5 mL); and the reaction
was allowed to stir for 5 h at -40 °C. Purification through silica
gel flash chromatography (7:1 to 2:1 hexanes-EtOAc) afforded a
22:1 product ratio of 22a:23a. Both 22a (39 mg, 67%) and 23a
(2.0 mg, 3%) were isolated as white solids. In addition, minor
amounts of 24a (8 mg, 10%) and 26a (3 mg, 7%) were also isolated,
each as a white solid.
Conclusions
Data for 22a. The spectral data for compound 22a matched that
In these studies of site-selective thiocarbonylation, we have
established a number of important milestones. Initially, we
identified a reliable reagent combination that leads to consistent
and efficient thiocarbonylation reactions using phenyl chlo-
rothionoformate as a reagent and a combination of NMI and
FeCl3 (each in substoichiometric quantities) as co-catalysts.
Importantly, we then showed that site-selectivity of thiocarbo-
nylation may be modulated in a catalyst-dependent fashion, and
in particular, peptidic structures containing the N-alkylimidazole
substructure are critical variables in screening and optimization.
Furthermore, in selected cases, we showed that one could
observe reversals of inherent selectivity such that catalyst control
which had been previously reported.32
4,6-O-Benzylidene 3-Mono(thiocarbonate) R-Methyl Gluco-
side, 23a. General Procedure B for thiocarbonylation was followed;
glucose derivative 12a (30 mg, 0.11 mmol) was employed as
starting material with peptide 28 (32 mg, 0.022 mmol), phenyl
(30) (a) Karl, H.; Lee, C. K.; Khan, R. Carbohydr. Res. 1982, 101, 31-
38. (b) Adinolfi, M.; De Napoli, L.; Di Fabio, G.; Iadonisi, A.; Montesarchio,
D. Org. Biomol. Chem. 2004, 2, 1879-1886.
(31) (a) Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew. Chem., Int.
Ed. 2001, 40, 2824-2827. (b) See ref. 12.
(32) Petra´kova´, E.; Glaudemans, C. P. J. Glycoconjugate J. 1994, 11,
17-22.
J. Org. Chem, Vol. 73, No. 5, 2008 1781

Sa´nchez-Rosello´ et al.
chlorothionoformate (22 µL, 0.165 mmol), 1,2,2,6,6-pentamethyl
piperidine (40 µL, 0.22 mmol), and FeCl3 (2.7 mg, 0.0165 mmol)
in CH2Cl2 (1.0 mL); and the reaction was allowed to stir for 5 h at
-25 °C. Purification through silica gel flash chromatography (7:1
to 2:1 hexanes-EtOAc) afforded a 1:6.6 product ratio of 22a:23a.
Both 22a (4.0 mg, 8%) and 23a (24 mg, 53%) were isolated as
white solids. In addition, minor amounts of 24a (3 mg, 5%) and
26a (3 mg, 8%) were also isolated, each as a white solid.
Compound 29. General Procedure for deoxygenation was
followed, and glucose derivative 22a (54 mg, 0.13 mmol) was
employed as starting material with AIBN (6.4 mg, 0.039 mmol)
and tributyltin hydride (100 µL, 0.39 mmol). Compound 29 was
isolated as a white solid (24 mg, 70%). The spectral data for
compound 29 matched that which had been previously reported.34
Compound 30. General Procedure for deoxygenation was
followed, and glucose derivative 23a (50 mg, 0.12 mmol) was
employed as starting material with AIBN (6.0 mg, 0.036 mmol)
and tributyltin hydride (95.0 µL, 0.36 mmol). Compound 30 was
isolated as a white solid (23 mg, 72%). The spectral data for
compound 30 matched that which had been previously reported.35
Compound 31. General Procedure for deoxygenation was
followed, and glucose derivative 24a (79 mg, 0.14 mmol) was
employed as starting material with AIBN (7.0 mg, 0.042 mmol)
and tributyltin hydride (110 µL, 0.42 mmol). Compound 31 was
isolated as a white solid (23 mg, 66%).
1
Data for 23a. Mp 97-101 °C; H NMR (CDCl3, 500 MHz) δ
7.51-7.49 (m, 2H), 7.41-7.27 (m, 6H), 7.12-7.10 (m, 2H), 5.98
(t, J ) 9.5 Hz, 1H), 5.56 (s, 1H), 4.89 (d, J ) 3.5 Hz, 1H), 4.35
(dd, J ) 4.7, 10.4 Hz, 1H), 3.98-3.91 (m, 2H), 3.83-3.77 (m,
2H), 3.52 (s, 3H), 2.31 (d, J ) 9.5 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ 195.8, 153.5, 136.9, 129.4, 129.1, 128.2, 126.5, 126.2,
101.5, 100.1, 82.1, 78.7, 71.9, 68.9, 62.7, 55.7, 53.4; IR (film, cm-1
)
3457, 2917, 1483, 1283, 1201, 1070, 1050; TLC Rf 0.22 (2:1
hexanes-EtOAc); [R]20 +84.1 (c 1.0, CHCl3); HRMS calcd for
D
[C21H23O7S H]+ requires m/z 419.1165; found 419.1167 (ESI+).
4,6-O-Benzylidene 2,3-Bis(thiocarbonate) R-Methyl Gluco-
1
Data for 31. Mp 199-202 °C; H NMR (CDCl3, 400 MHz) δ
7.50-7.48 (m, 2H), 7.39-7.34 (m, 3H), 5.57 (s, 1H), 4.70 (d, J )
3.3 Hz, 1H), 4.22 (dd, J ) 4.5, 10.1 Hz, 1H), 3.83 (dt, J ) 4.8, 9.7
Hz, 1H), 3.72 (t, J ) 10.2 Hz, 1H), 3.63-3.57 (m, 1H), 3.38 (s,
3H), 2.02-1.84 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 137.7,
129.0, 128.3, 126.2, 101.9, 97.9, 78.3, 69.6, 64.8, 54.6, 29.5, 24.0;
IR (film, cm-1) 2946, 2901, 2868, 1377, 1123, 1095, 1054, 997,
919, 694; TLC Rf 0.44 (2:1 hexanes-EtOAc); [R]20D +93.5 (c 0.62,
CHCl3); HRMS calcd for [C14H18O4 Na]+ requires m/z 273.1103;
found 273.1112 (ESI+).
1
side, 24a. Mp 58-60 °C; H NMR (CDCl3, 500 MHz) δ 7.41-
7.39 (m, 2H), 7.33-7.13 (m, 9H), 7.03-7.01 (m, 2H), 6.95-6.93
(m, 2H), 6.22 (t, J ) 9.6 Hz, 1H), 5.57 (dd, J ) 3.8, 9.5 Hz, 1H),
5.48 (s, 1H), 5.17 (d, J ) 3.8 Hz, 1H), 4.27 (dd, J ) 4.7, 10.3 Hz,
1H), 3.97 (dt, J ) 4.7, 10.0 Hz, 1H), 3.83 (t, J ) 9.6 Hz, 1H), 3.74
(t, J ) 10.2 Hz, 1H), 3.40 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 194.4, 194.3, 153.5, 153.4, 136.7, 129.6, 129.4, 129.1, 128.2,
126.8, 126.6, 126.2, 121.8, 121.7, 101.7, 96.9, 79.6, 79.1, 78.5,
68.8, 62.4, 55.7; IR (film, cm-1) 2918, 1487, 1454, 1272, 1225,
1192, 1148, 1123; TLC Rf 0.56 (2:1 hexanes-EtOAc); [R]20D -30.5
(c 1.0, CHCl3); HRMS calcd for [C28H27O8S2 H]+ requires m/z
555.1147; found 555.1145 (ESI+).
Acknowledgment. This work is supported by the NIH (GM-
068649). M.S.-R. would like to thank the Ministerio de
Educacio´n y Ciencia of Spain for a postdoctoral fellowship.
Compound 26a. The spectral data for compound 26a matched
that which had been previously reported.33
Supporting Information Available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for compounds
8, (()-13, 20, 21, 22b-24b, 26b, 33, 34, 35, 36, 38, and 39. This
material is available free of charge via the Internet at http://pubs.
acs.org.
General Procedure for the Deoxygenation Reaction. To a
solution of the corresponding mono- or bis(thiocarbonate) (1 equiv)
in toluene (4 mL) were added tributyltin hydride (3 equiv) and
AIBN (0.3 equiv), and the mixture was heated at reflux for 3 h.
Solvent was then removed under reduced pressure, and the resulting
residue was purified by silica gel flash chromatography (3:1 to 2:1,
hexanes-EtOAc).
JO702334Z
(34) Minami, A.; Eguchi, T. J. Am. Chem. Soc. 2007, 129, 5102-5107.
(35) Lee, E.; McArdle, P.; Browne, P.; Gavin, N. Carbohydr. Res. 1989,
191, 351-356.
(33) Tsuda, Y.; Noguchi, S.; Kanemitsu, K.; Sato, Y.; Kakimoto, K.;
Iwakura, Y.; Hosoi, S. Chem. Pharm. Bull. 1997, 45, 971-980.
1782 J. Org. Chem., Vol. 73, No. 5, 2008