Preparation of enantioenriched tetraols and triolamines from a common epoxide

Article abstract of DOI:10.1016/j.tetlet.2013.07.001

We identify a silylcyclopentene oxide that is amenable to several distinct asymmetric catalytic transformations providing access to enantio-enriched tetraol and triol-amines. The sequence employed allows for selective protection of one amine or alcohol from the four heteroatoms that are introduced into the carbon scaffold.

Full text of DOI:10.1016/j.tetlet.2013.07.001

Tetrahedron Letters 54 (2013) 5014–5017
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of enantioenriched tetraols and triolamines
from a common epoxide
⇑
Makan Kaviani-Joupari, Michael P. Schramm
Department of Chemistry and Biochemistry, California State University Long Beach, 1250 Bellflower Blvd., Long Beach, CA 90840, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We identify a silylcyclopentene oxide that is amenable to several distinct asymmetric catalytic transfor-
mations providing access to enantio-enriched tetraol and triol-amines. The sequence employed allows for
selective protection of one amine or alcohol from the four heteroatoms that are introduced into the car-
bon scaffold.
Received 3 June 2013
Revised 24 June 2013
Accepted 1 July 2013
Available online 6 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Chiral polyols
Chiral polyolamines
Silylcyclopentene oxide
Jacobsen’s catalyst
Enantioenriched polyols and polyol amines make up important
classes of building blocks for the preparation of biologically impor-
tant natural products. Of recent interest has been work toward
polyketides (and polyketide-like) macrolides where small polyol
fragments have proven versatile.1,2 Selectively protected benzyl
ether polyols have been incorporated into the total syntheses of
antitumor antibiotics azinothricin and kettapeptin.3 Polyol amines
such as 2-amino-1,3,4-butantriol are central to one preparation of
the HIV-Protease Inhibitor Nelfinavir.4 These small building blocks
have many other applications including as hypoxic cell radiosensi-
tizers,5 in large macrolactams that demonstrate beta-secretase 1
(BACE-1) inhibition,6 as a building block for phytosphingosines,7
and as synthons for azasugars.8 Applications where selective func-
tionalization of the amine group as an amide9 or triazole10 have
biological significance.
Figure 1. Desymmetrization of 1 and preparation of alkyl and aryl substituted
polyols 3.11
few racemic reactions that would be suitable for diversifying this
epoxide, most notable was azide addition.12,13 In parallel we be-
came interested in asymmetric azide addition to cycloalkane
oxides.14 We began our work at the confluence of these reports.
The highly effective salen catalyst developed by Jacobsen has
been used very effectively for the asymmetric ring opening of
epoxides15 including cyclopentaneoxide and cyclohexaneoxide.
Nucleophiles such as azide,14 acetate, and benzoate16 have been
utilized in these reactions. Jacobsen identified Cr catalyst 4 as
widely applicable for enantioselective ring opening with azide to
cyclohexaneoxide, cyclopentaneoxide, tetrahydrofuranoxide, and
pyrollidineoxide.14 We began our investigation with meso silylcycl-
openteneoxide 1 with the expectation that silicon removal would
ultimately afford polyol azides or polyol amines.14
In identifying a common building block for these diverse
applications we turned our attention to the highly innovative
strategy of desymmetrizing meso epoxide 1 with chiral amide
base to give alcohol 2 in high ee (Fig. 1).11 Alcohol 2 was further
elaborated and the silicon center upon oxidation yielded diverse
alkyl substituted chiral tetraols 3 in greater than 70% yield
(where R = butyl, isopropyl, allyl, Ph, and H). This strategy had
immediate applications and advantages to the preparation of
(À)-pinolidoxin.1
We began an examination to determine if other high-impact
transformations were possible for substrate 1. We identified a
Treatment of 1 with 2 mol % of Cr catalyst (R,R)-4 (Fig. 2) at
elevated temperature resulted in formation of both the desired
alcohol 5 as well as TMS ether 6 in a total of 80% isolated yield
⇑
Corresponding author. Tel.: +1 562 985 1866.
E-mail address: michael.schramm@csulb.edu (M.P. Schramm).
URL: http://chemistry.csulb.edu/schramm/ (M.P. Schramm).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.001

M. Kaviani-Joupari, M. P. Schramm / Tetrahedron Letters 54 (2013) 5014–5017
5015
Figure 2. Enantioselective ring opening of epoxide 1 with azide and Jacobsen’s catalyst 4 (see Table 1).
Table 1
Reaction outcome and conditions for the asymmetric ring opening of epoxide 1 with TMS azide and catalyst 4 (see Table 1)
Entry
Catalyst loading
T (°C)
Time
Alcohol 5 (yield)a
% eeb of 5
TMS ether 6 (yield)c
1
2
3
2
2
15
50
22
À70
11 h
12 h
5 d
58%
16
68
84
22%
—
—
97%d
59%e
a
b
c
Isolated yield after column chromatography.
Determined by Mosher ester analysis.17
Isolated yield after column chromatography, a brief workup with camphorsulfonic acid in methanol quantitatively converts TMS ether 6 into alcohol 5 without loss of ee.
TMS ether hydrolyzed to alcohol prior to column chromatography.
d
e
Corrected isolated yield after recovery of 57% of starting material 1, trans chloro alcohol was isolated in 15% yield in addition to the desired alcohol 5, no TMS ether was
isolated (see ESI for complete details).
and low ee (Table 1, entry 1). The TMS ether 6 can be readily
hydrolyzed with camphorsulfonic acid in methanol as part of the
work up procedure to produce alcohol 5 quantitatvely.14 The reac-
tion was slightly slower at room temperature, but on 0.5 g scale the
desired azido alcohol was isolated in 97% yield (entry 2) after
hydrolysis of TMS, with 68% ee by Mosher ester analysis (see ESI
for full details). At À15 °C the reaction slowed with only modest
increase in ee (not shown), at À70 significant starting material
remained after 4 days and a trans chloro alcohol (see ESI) was iso-
lated in 15% yield. The chloro alcohol product likely arises from the
chloride ligand of 4 attacking the epoxide. Despite these issues, an
increase to 84% ee was achieved with a yield of the desired alcohol
in 59% after accounting for recovered starting material. We deter-
mined absolute stereochemistry at the alcohol stereocenter to be
(R) by a method described below (Fig. 3).
Having demonstrated the preparation of enantioenriched trans
azido alcohol 5 we were eager to attempt oxidation and removal of
the silicon core. We attempted the Woerpel18 oxidation conditions
as used by Kozmin11 for the preparation of tetraols 3, and instead
of desired triol azide 7 we isolated exclusively the chiral allylic diol
8 (Fig. 3). It seems under these conditions azide presents a facile
leaving group for elimination.
optical rotation data for this alcohol were particularly sensitive to
experimental conditions, thus our confidence in ee lies with
Mosher analysis.
We tried several oxidation procedures to overcome the elimina-
tion of azide, including KF with hydrogen peroxide, but these gave
significant amounts of 8. Treatment of 5 with MCPBA21 under basic
conditions however effected the desired transformation to 7 in 55%
yield without unwanted elimination. A complete mechanistic
explanation for conversion of 5 into 8 has not been explored, but
it is likely oxidation to pentacoordinate silicon precedes elimina-
tion as alkenylsilanes treated with HOOH, KF, and KHCO3 give car-
bonyl compounds.22 Thus if 5 underwent E2 elimination to give a
silylalkene, subsequent oxidation should give products that we
have not observed.23 Alternatively there may be two different out-
comes depending on selection of oxidant. In the case of t-BuOOÀ,
carbon silicon bond breaking and elimination of azide would ratio-
nalize the alkene present in 8.24 In the case of MCPBAÀ, the stan-
dard oxygen insertion reaction could account for the terminal
alcohol.21 The differential behavior could be the result of either
the leaving group ability of t-BuOÀ versus 3-chlorobenozateÀ, or
the inherent nucleophilicity difference between the two peroxy
species.
The unexpected alcohol 8 is a useful building block for a variety
of synthetic applications.19 The isolation of 8 allowed us to readily
assign absolute stereochemistry at the alcohol stereocenter as
introduced in the asymmetric step (Fig. 2). The literature optical
rotation20 for (S)-8 is À44° and we found our sample to have
+20.6°, which proves (R) stereochemistry at the alcohol center with
an ee of 47%. This result is consistent with ee of the starting azide 5
(58% in this case) as determined by Mosher ester analysis. Precise
Azide 7’s diastereomers have previously been prepared from
L
D
or
-diethyltartrate and used toward the preparation of azasugars.8
At this stage we explored modifications to the azide group of 5 to
expand the utility of this transformation and to uncover oxidation
conditions that avoid unwanted eliminations. Azide alcohol 5 read-
ily underwent tin chloride reduction in HCl25 to give the corre-
sponding amine that was acylated with benzoyl chloride to give
amide 9 in good yield. Oxidation with Na t-butylperoxide gave
the desired amide triol 10 in acceptable yield (Fig. 4). Alternatively,
triazole formation26 with 1-hexyne and oxidation gave 11 and 12
in high yields, respectively. These two nitrogen triols (10 and 12)
have direct application to medicinal chemistry.9,10 Reduction of 5
with tin chloride gave the amine 13 in 75% yield, subsequent oxi-
dation cleanly gave the expected amino triol 14 (TLC and crude
NMR analysis), but challenges with isolation have as of yet only
provided this compound in small quantities (Fig. 5). The methyl
carbamate of 13 was also prepared (results not shown).
In addition to azide, we explored the use of acetate toward
functionalizing epoxide 1 using asymmetric ring opening cataly-
sis.16 As previously reported, the use of Co(III) salen complex was
Figure 3. Oxidation of 5 to produce azido triol 7 and unexpected allylic diol 8.

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M. Kaviani-Joupari, M. P. Schramm / Tetrahedron Letters 54 (2013) 5014–5017
Figure 4. Preparation of 2-amide and 2-triazole 1,3,4-butantriols 10 and 12.
Figure 5. Access to 2-amino-1,3,4-butantriol 14.
Table 2
Reaction outcome and conditions for the asymmetric ring opening of epoxide 1 with acetate and catalyst 10 (see Fig. 6)
Entry
Catalyst loading
T (°C)
Time
Alcohol 16 (yield)a
% eeb of 16
Recovered 1 (yield)
1
2
3
10
10
10
0
À20
À70
12 h
3 d
6 d
71%
73%
16%c
48
62
65
—
—
79%
a
b
c
Isolated yield after column chromatography.
Determined by Mosher ester analysis.17
Uncorrected isolated yield after recovery of 79% of starting material 1.
Figure 6. Enantioselective ring opening of epoxide 1 with acetate and Jacobsen’s Co catalyst 15 (See Table 2).
most efficacious. Epoxide 1 was treated with 10 mol % catalyst
(R,R)-15 at 0 °C for 12 h, acetate alcohol 16 was isolated in 71%
yield (Table 2, entry 1). The ee at the newly introduced stereocen-
ter was determined to be 48% under these conditions. Lowering the
temperature of the reaction resulted in minor improvement in ee
(Table 2, entries 2 and 3). At À70 °C the reaction rate slowed
drastically.
insertion at the second carbon center attached to silicon have been
previously observed for the strained dimetylsilacyclobutane.29 In
that report, oxidation with hydrogen peroxide, KF, and KHCO3 gave
1,3-propanediol and 1-propanol in a 1.5:1 ratio. The regio chemis-
try of 20 was determined by comparison to a literature report30 as
well as through acetonide formation; the acetonide product of 20
is consistent with a vicinal diol, not the alternative 1,3-diol (see
ESI for full details).
The preparation of enantiopure building blocks remains a fun-
damental area of importance for synthetic chemistry. In many
applications of asymmetric catalysis, feedstocks derived from sim-
ple petroleum products are converted into materials with very di-
verse properties. We started from a common building block, meso
silylcylic epoxide 1 and demonstrated the application of two differ-
ent asymmetric addition reactions. Further elaboration demon-
strated that a variety of selective protection strategies could be
employed before the final oxidation and removal of the silicon
core. This first report demonstrates a variety of distinct chemical
species with moderate ee and good yield. One major variable that
remains untested for substrate 1 is the role of solvent in both the
addition of azide (Fig. 2) and acetate (Fig. 6). This is one area we
Despite the disappointing ee of this reaction we decided to test
a few strategies toward developing useful chiral building blocks.
Our attempt to isolate mono-acetate triol from treatment of 16
with Na t-butylperoxide failed to yield the desired triol, instead
giving the elimination product allylic diol 8 (Fig. 7). Optical rota-
tion confirmed (R) stereochemistry as was observed in Figure 3.
Alternatively we benzylated the free alcohol using a silver(I) med-
iated alkylation giving benzyl ether 17 in 86% yield.27 Hydrolysis of
acetate 17 in methanol gave the free alcohol 18 in 78% yield. This
ether was far more robust, surviving oxidation with tBuOONa to
give 2-O-benzyl-D
-threitol 1928 in 30% yield. This particular build-
ing block has applications for the total synthesis of (+)-azinothricin
and (+)-kettapeptin.3 In addition to 19 we isolated monobenzyle-
ther diol 20 in 27% yield. The oxidation at one carbon and hydrogen

M. Kaviani-Joupari, M. P. Schramm / Tetrahedron Letters 54 (2013) 5014–5017
5017
Figure 7. Preparation of 2-O-benzyl-
D
-threitol 19 and benzylether diol 20.
7. Lu, X.; Byun, H.-S.; Bittman, R. J. Org. Chem. 2004, 69, 5433–5438.
8. Calderon, F.; Doyagüez, E. G.; Fernandez-Mayoralas, A. J. Org. Chem. 2006, 71,
6258–6261.
are currently exploring. The other variable that might appear to be
significant is the role of the spectator phenyl groups on epoxide 1.
We have some initial evidence that the role of these groups will
have little consequence in the desymmetrization reactions re-
ported herein. Additionally, they played no discernable role in
the desymmetrization of 1 by chiral amide base as demonstrated
in Figure 1.11 We believe that the variety of chiral polyol and polyol
amine building blocks reported herein are just the beginning and
the results of our continued exploration will be reported in a
sequel.
9. Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa, E.; Yamaji, K.;
Koezuka, Y.; Kobayashi, E.; Fukushima, H. J. Med. Chem. 1995, 38, 2176–2187.
10. Lee, T.; Cho, M.; Ko, S.-Y.; Youn, H.-J.; Baek, D. J.; Cho, W.-J.; Kang, C.-Y.; Kim, S.
J. Med. Chem. 2007, 50, 585–589.
11. Liu, D.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4757.
12. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557–1560.
13. Yadav, J. S.; Reddy, B. V. S.; Jyothirmai, B.; Murty, M. S. R. Tetrahedron Lett. 2005,
46, 6559–6562.
14. Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc.
1995, 117, 5897–5898.
15. Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421–431.
16. Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.; Tokunaga, M.
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Acknowledgment
17. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549.
18. Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044–6046.
19. There are currently 31 references for the preparation of enantioenriched
polylol 8 and 29 publications using it as a building block.
20. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A.
E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
21. Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.; Yoshida, J.; Kumada,
M. Tetrahedron 1983, 39, 983–990.
We thank the CSU Fullerton Department of Chemistry and Bio-
chemistry and NSF MRI CHE-0521665 for special NMR use.
Supplementary data
Supplementary data associated (Complete experimental proce-
dures with tabulated 1H, 13C, and MS data are included for all new
compounds. 1H, 13C, and DEPT-135 spectra are included for all new
compounds. Ee calculation by Mosher analysis and absolute ste-
reochemical determination are included.) with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.07.001.
22. Marshall, J. A.; Yanik, M. M. J. Org. Chem. 2001, 66, 1373–1379.
23. Not observed.
24. Possible mechanisms for differential oxidation outcomes.
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