A stereo-divergent route to aminocyclopentitol derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.05.103

A stereo-divergent synthetic strategy based on diastereoselective vinylation of an α-amino aldehyde, ring-closing metathesis reaction and diastereoselective dihydroxylation reaction as key steps has been developed for the synthesis of three aminocyclopentitol derivatives of chemical and biological relevance.

Full text of DOI:10.1016/j.tetlet.2011.05.103

Tetrahedron Letters 52 (2011) 3942–3944
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A stereo-divergent route to aminocyclopentitol derivatives
⇑
Shital K. Chattopadhyay , Ayan Bandyopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereo-divergent synthetic strategy based on diastereoselective vinylation of an
a-amino aldehyde,
Received 29 April 2011
Revised 20 May 2011
Accepted 22 May 2011
Available online 30 May 2011
ring-closing metathesis reaction and diastereoselective dihydroxylation reaction as key steps has been
developed for the synthesis of three aminocyclopentitol derivatives of chemical and biological relevance.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopentitol
Asymmetric synthesis
Amino acids
Ring-closing metathesis
Aminocyclopentitol structures are present in a number of natural
products such as mannostatin1 (1) and trehazolin2 (2, Fig. 1) which
display high activity in glycosidase inhibition, a property relevant
to the treatment of myriad diseases like type 2 diabetes mellitus,
metastatic cancer, viral and bacterial infections like neuraminidase
activity and human innunodeficiency.3 Inspired by these lead com-
pounds, a library of aminocyclopentitol derivatives have been pre-
pared and evaluated.4 These studies have revealed that regio- and
streochemical diversities within the cyclic framework may subtly
influence their biological activity, and sometimes a desired potency
is achieved through structural manipulation based on mechanistic
studies.5 Synthetic entry to this pharmaceutically important scaf-
fold, therefore, continues to be reported.6 However, development
of common synthetic route to various stereoisomeric cyclopentitol
derivatives remains important. Herein, we wish to report a simple
HO
HO
OH
SMe
HO
HO
OH
N
OH
NH2
O
NHR
1, Mannostatin A
2, Trehazolin
Figure 1.
assigned syn-configuration based on the assumption that chelation
control10 had prevailed and with further support from the following
synthetic work.
Thus, the diene 7 was subjected to undergo ring-closure with
Grubbs’ first generation catalyst benzylidene bistricyclohexyl
phosphinoruthenium(IV) dichloride11 9 to obtain the correspond-
ing cyclopentene 10 in good yield. Deprotection of the TBDPS
entry to a few such derivatives from L-serine.
Our synthesis started from the known7 Garner’s aldehyde-
derived allyl alcohol 3 (Scheme 1) which was protected as its tert-
butyldiphenylsilyl (TBDPS) ether 4. The oxazolidine ring in com-
pound 4 was then opened with acid to provide the amino alcohol 5
which was quickly oxidised with Dess–Martin periodinane8 follow-
group from 10 then led to the dihydroxy derivative 11, [a]
D
À33.0 (c 0.52, CHCl3). An identical sequence of reactions on the
minor diene 8 provided the isomeric diol 13. Comparison of 1H
and 13C NMR spectra of each of the diols 11 and 13 quickly re-
vealed the symmetry present in 13 and hence the configuration
of the new stereocentre in 7 and 8.
ing precedence.9 The aldehyde 6, [
a]
D À53.3 (c 1.35, CHCl3), proved
to be essentially pure and could be stored, if necessary, at À20 °C for
7 days without appreciable racemisation as judged from repeated
spectroscopic and optical measurement experiments. For practical
purpose, it was used as such in the next step. Addition of vinylmag-
nesium bromide to this aldehyde then gave a separable mixture of
the allyl alcohols 7 and 8 in the ratio of 7:3. The major isomer was
Similarly, starting from the known allyl alcohol 14 (Scheme 2),
the chiral
a-amino aldehyde 17, [
a
]
D
À46.1 (c 1.25, CHCl3), was
prepared in an overall yield of 66% over three convenient steps.
Compound 17 too proved to be isolable and stable enough for char-
acterisation and it could be stored also at À20 °C for a week. Addi-
tion of vinylmagnesium bromide to 17 proceeded to deliver the
allyl alcohol 18 as a single isolable product and in distereomerical-
ly pure form as judged from its spectroscopic and chromatographic
⇑
Corresponding author. Fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.103

S. K. Chattopadhyay, A. Bandyopadhyay / Tetrahedron Letters 52 (2011) 3942–3944
3943
OR
HO
HO
OTBDPS
OH
OH
OTBDPS
O
i
iii
10
12
ii
iii
iv
HO
BocHN
O
or ii
HO
HO
OTBDPS
OH
NBoc
BocHN
NHBoc
NHBoc
6
21
5
3, R = H
4
22
i
, R = TBDPS
HO
HO
OH
OH
OTBDPS
OTBDPS
OH
OH
iii
i
HO
HO
+
OTBDPS
OH
BocHN
BocHN
NHBoc
NHBoc
23
7
24
8
v
vi
7
HO
HO
HO
HO
OH
OTBDPS
NHBoc
10
O
O
HO
OH
NHBoc
iv
i
19
11
HO
OTBDPS
HO
OTBDPS
NHBoc
NHBoc
vi
v
26
25
OH
NHBoc
13
8
OTBDPS
NHBoc
HO
OH
12
iii
25
HO
OH
Scheme 1. Reagents and conditions: (i) TBDPSCl, imidazole, CH2Cl2, rt, 3 h, 98%; (ii)
p-TsOH (0.3 equiv), MeOH, rt, 2 h, 80%; (iii) Dess–Martin periodinane, CH2Cl2, rt,
0.5 h, 94%; (iv) vinylmagnesium bromide, À78 to À20 °C, 3 h, 72%; (v) 9 (5 mol %),
CH2Cl2 (0.01 M), rt, 12 h, 85% for 10, 79% for 12; (vi) n-Bu4N+FÀ, THF, rt, 4 h, 93% for
11, 89% for 13.
NHBoc
27
Scheme 3. Reagents and conditions: (i) OsO4 (5 mol%), N-methylmorpholine-N-
oxide (NMMO) (2 equiv), acetone–water (5:1), 24 h, 96% for 21; 94% for 23; 97% for
25; (ii) OsO4 (5 mol %), EDTA, CH2Cl2, 24 h, 81%; (iii) n-Bu4N+FÀ, THF, rt, 4 h, 89% for
22, 87% for 24, 97% for 27; (iv) 2,2-dimethoxypropane, p-TsOH, CH2Cl2, rt, 0.5 h,
96%.
(HPLC) behaviour. The configuration of the new stereocentre in 18
was similarly assigned as syn and was also corroborated by its con-
version to the meso-diol 20 through the two-step sequence out-
lined above, that is, ring-closing metathesis (RCM) leading to 19
and then deprotection of the TBDPS group.
the TBDPS group from 23 then led to the meso-aminocyclopentitol
derivative 24. The cyclopentene derivative 19 also showed very
similar behaviour during dihydroxylation providing 25 as the only
product in an overall yield of 41% over six steps. The latter, on
treatment with 2,2-dimethoxypropane in the presence of a cata-
lytic amount of p-TSA provided a single acetonide 26 in near quan-
titative yield. Deprotection of the TBDPS group from 25 then
provided the meso-diol 27. This information, that is, formation of
a single acetonide from 25, and symmetric nature of the diol 27
helped us to assign the stereochemistry of the triol 25 as depicted.
In conclusion, we have developed a short and efficient synthetic
Having access to the stereo-defined aminocyclopentene deriva-
tives 10, 12 and 19, we focussed on their conversion to the targeted
aminocyclopentitol derivatives through a possible diastereoselec-
tive dihydroxylation reaction of the double bond present in these
structures Thus, dihydroxylation of 10 (Scheme 3) under Upjohn
conditions12 led to the formation of a single diastereomer in 96%
yield which was assigned configuration based on the assumption
that dihydroxylation has taken place opposite to the bulky OTBDPS
group. Dihydoxylation under hydroxy directed conditions as re-
ported by Donohoe et al.13 also produced the same stereoisomer,
as expected, albeit in lower yields. Deprotection of the TBDPS group
from 21 then smoothly led to the aminocyclipentitol derivative 22
in very good yield. Similarly, dihydroxylation of the cyclopentene
derivative 12 under analogous conditions led to the formation of
a single diastereomer whose stereochemistry was assigned as in
23 based on the belief that dihydroxylation has taken place from
the side opposite to the adjacent bulky groups. Deprotection of
protocol involving stereoselective vinylation of a a-chiral aldehyde
leading to three stereo-defined aminocyclopentene-1,3-diol deriv-
atives viz. 10, 12 and 19 which may be considered as important
building blocks based on similar applications.14 Dihydroxylation
of each of these three cyclopentene derivatives was found to be
extremely facile and highly stereoselective providing access15 to
the triols 21, 23 and 25 which may also be considered as useful
building blocks in the design and synthesis of aminocyclopentitol
OR
OTBDPS
OTBDPS
O
iii
ii
iv
O
HO
BocHN
NBoc
BocHN
17
14, R = H
16
i
15, R = TBDPS
OTBDPS
OH
vi
v
HO
HO
OH
OTBDPS
NHBoc
19
NHBoc
BocHN
18
20
Scheme 2. Reagents and conditions: (i) TBDPSCl, imidazole, CH2Cl2, rt, 3 h, 93%; (ii) p-TsOH (0.3 equiv), MeOH, rt, 3 h, 77%; (iii) Dess–Martin periodinane, CH2Cl2, rt, 0.5 h,
92%; (iv) vinylmagnesium bromide, À78 to À20 °C, 3 h, 74%; (v) 9 (5 mol %), CH2Cl2 (0.01 M), rt, 12 h, 86%; (vi) n-Bu4N+FÀ, THF, rt, 4 h, 95%.

3944
S. K. Chattopadhyay, A. Bandyopadhyay / Tetrahedron Letters 52 (2011) 3942–3944
11. (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100; (b)
Grubbs, R. H. Tetrahedron 2004, 60, 2117; For a recent review on the RCM of
hetero atom-tethered dienes, see: (c) Chattopadhyay, S. K.; Karmakar, S.;
Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919.
12. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 17, 1973.
13. Donohoe, T. J.; Moore, P. R.; Waring, M. J. Tetrahedron Lett. 1997, 38, 5027.
14. (a) Lu, H.; Mariano, P. S.; Lam, Y.-F. Tetrahedron Lett. 2001, 42, 4755; (b) Cho, S.
J.; Ling, R.; Kim, A.; Mariano, P. S. J. Org. Chem. 2000, 65, 1574; (c) Ling, R.;
Mariano, P. S. J. Org. Chem. 1998, 63, 6072.
derivatives of interest. Ease of availability of starting materials, use
of less expensive reagents, high yields in most of the conversions,
useful level of stereoselectivity, pre-determined mode of ring-clo-
sure, divergence and diversity in the stereochemical pattern are
some of the attractive features of our protocol which may comple-
ment to those existing in the literature for the preparation of such
types of compounds.
15. All new compounds reported gave satisfactory spectroscopic and/or analytical
data. Compound 7: [
a] +21.8 (c 0.9, CHCl3), IR (CHCl3): 3445, 1715, 1501,
D
Acknowledgements
1170, 702 cmÀ1 1H NMR (400 MHz, CDCl3): d 7.65–7.63 (m, 4H), 7.44–7.35
.
(6H, m), 5.85–5.68 (2H, m), 5.32–5.27 (1H, dd, J = 16.8, 1.6 Hz), 5.16–5.0 (4H,
m), 4.60–4.48 (2H, m), 3.53–3.30 (2H, m), 1.38 (9H, s), 1.09 (9H, s). 13C NMR
(125 MHz, CDCl3): 156.0, 137.4, 136.9, 136.0, 132.9, 132.6, 130.1, 129.9, 127.8,
127.6, 117.6, 116.0, 79.3, 77.5, 70.6, 57.9, 28.3, 27.1, 19.4. M.S (TOF MS ES+):
504 (M+Na). Anal. Calcd for C28H39NO4Si: C, 69.82; H, 8.16; N, 2.91. Found: C,
69.98; H, 8.28; N, 3.20.
We are thankful to DST (Grant No. SR/S1-OC/35/2009), Govern-
ment of India, for financial assistance and CSIR for fellowship to
one of us (A.B.).
Compound 8: [a] ,
D +7.3 (c 0.55, CHCl3). IR (CHCl3): 3444, 1705, 1505, 702 cmÀ1
References and notes
1H NMR (400 MHz, CDCl3): d 7.73–7.62 (4H, m), 7.45–7.34 (6H, m), 5.9–5.82
(1H, m), 5.77–5.71 (1H, m), 5.25 (1H, d, J = 16.4 Hz), 5.18–5.05 (3H, m), 4.64
(1H, br s), 4.34–4.29 (2H, m), 3.75–3.64 (1H, m), 2.67 (1H, d, J = 6 Hz) 1.40 (9H,
s), 1.07 (9H, s). 13C NMR (100 MHz, CDCl3): d 156.3, 137.3, 137.1, 136.0, 135.9,
133.4, 133.2, 130.0, 129.7, 127.7, 127.5, 117.5, 115.9, 79.5, 74.9, 72.8, 59.6,
28.3, 27.1, 19.4. MS (TOF MS ES+): 504 (M+Na). Anal. Calcd for C28H39NO4Si: C,
69.82; H, 8.16; N, 2.91. Found: C, 70.06; H, 8.32; N, 3.25.
1. Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morishima, H.; Nagai, M.; Hamada, M.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1989, 42, 883.
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McDonald, M.; Fernley, R. T.; Varghese, J. N.; Colman, P. M. J. Med. Chem. 2002,
45, 2207.
Compound 18: [
a
]
D
À3.5 (c 0.84, CHCl3). IR (CHCl3): 3439, 1698, 1505, 1367,
1171, 1112, 702 cmÀ1
.
1H NMR (400 MHz, CDCl3): d 7.68–7.63 (4H, m), 7.44–
4. For some reviews, see: (a) Bereciber, A.; Grandjean, C.; Sriwardena, C. Chem.
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Martin, O. R. Curr. Top. Med. Chem. 2003, 3, 541; (d) Blaser, A.; Reymond, J.-L.
Org. Lett. 2000, 2, 1733; (e) Leroy, E.; Reymond, J.-L. Org. Lett. 1999, 1, 775; (f)
Blaser, A.; Reymond, J.-L. Org. Lett. 2000, 2, 151.
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G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645; (b) Blaser, A.; Reymond, J.-L.
Synlett 2000, 817; (c) McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42,
1197; (d) Mehta, G.; Mohal, N. Tetrahedron Lett. 2001, 42, 4227; (e) Soengas, R.
G.; Estevez, J. C.; Estevez, R. J. Org. Lett. 2003, 5, 1423; (f) Kummeter, M.;
Kazmaier, U. Eur. J. Org. Chem. 2003, 3325; (g) Chiara, J. L.; de Garcia, I. S.;
Bastida, A. Chem. Commun. 2003, 1874; (h) Bojstrup, M.; Fanefjord, M.; Lundt, I.
Org. Biomol. Chem. 2007, 5, 3164; (i) Kim, I. S.; Li, Q. R.; Lee, J. K.; Lee, S. H.; Lim,
J. K.; Zee, O. P.; Jung, Y. H. Synlett 2007, 1711; (j) Chakraborty, C.; Vyavahare, V.
P.; Puranik, V. G.; Dhavale, D. D. Tetrahedron 2008, 64, 9574; (k) Reddy, Y. S.;
Kadigachalam, P.; Doddi, V. R.; Vankar, Y. D. Tetrahedron Lett. 2009, 50, 5827; (l)
Rao, J. P.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083.
7. (a) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979; (b) Herold, P. Helv. Chim.
Acta 1988, 71, 354; (c) Bandyopadhyay, A.; Pal, B. K.; Chattopadhyay, S. K.
Tetrahedron: Asymmetry 2008, 19, 1875.
7.34 (6H, m), 5.85–5.71 (2H, m), 5.23–5.10 (2H, m), 5.03–4.85 (3H, m), 4.45–
4.34 (2H, m), 3.62 (1H, br s), 2.47 (1H, br s), 1.42 (9H, s), 1.07 (9H, s). 13C NMR
(100 MHz, CDCl3): d 155.4, 136.8, 136.5, 135.0, 134.9, 132.6, 132.1, 128.9,
128.7, 126.6, 126.4, 116.3, 115.1, 78.4, 74.5, 71.1, 57.8, 27.3, 26.0, 18.4. M.S
(TOF MS ES+): 504 (M+Na). Anal. Calcd for C28H39NO4Si: C, 69.82; H, 8.16; N,
2.91. Found: C, 70.01; H, 8.29; N, 3.17.
Compound 22: Mp: 96 °C. [
a
]
.
À39.9 (c 0.31, MeOH). IR (KBr): 3359, 1686,
D
1677, 1534, 1367, 1171 cmÀ1
1H NMR (400 MHz, DMSO-d6): d 6.24 (d, 1H,
J = 8.5 Hz), 4.70 (d, 1H, J = 5.6 Hz), 4.56 (1H, d, J = 6.0 Hz), 4.48 (1H, d,
J = 6.4 Hz), 4.42 (1H, d, J = 4.4 Hz), 3.75–3.65 (4H, m), 3.57 (1H, q, J = 5.0 Hz),
1.38 (9H, s). 13C NMR (100 MHz, DMSO-d6): d 155.5, 77.4, 76.8, 73.9, 73.6, 70.1,
57.5, 28.3. HRMS (TOF MS ES+): obsd 272.1110 (M+Na); calcd 272.1110.
Compound 24: Mp: 88 °C. IR (KBr): 3436, 1683, 1521, 1280, 1247, 1171,
1078 cmÀ1 1H NMR (400 MHz, DMSO-d6): d 5.45 (1H, d, J = 9.2 Hz), 4.80 (2H, d,
.
J = 4.8 Hz), 4.60 (2H, d, J = 3.2 Hz), 3.96 (1H, q, J = 6.4 Hz), 3.74–3.71 (4H, m),
1.38 (9H, s). 13C NMR (100 MHz, DMSO-d6): d 154.9, 77.7, 76.5, 74.6, 51.9, 28.2.
HRM.S (TOF MS ES+): obsd 272.1113 (M+Na); calcd 272.1110.
Compound 25: [
a
]
D
À6.9 (c 0.58, CHCl3). IR (CHCl3): 3404, 1694, 1515, 1392,
1366, 1169, 1112, 702 cmÀ1
.
1H NMR (400 MHz, DMSO-d6): d 7.71–7.63 (4H,
m), 7.45–7.35 (6H, m), 6.62 (1H, d, J = 9.2 Hz), 4.98 (1H, d, J = 6.0 Hz), 4.73 (1H,
d, J = 5.2 Hz), 4.19 (1H, d, J = 4.0 Hz), 3.81 (1H, dd, J = 6.0, 2.4 Hz), 3.64–3.58
(3H, m), 3.54–3.50 (1H, m), 1.38 (9H, s), 1.10 (9H, s). 13C NMR (100 MHz,
CDCl3): d 157.0, 135.8, 133.3, 133.1, 130.1, 128.0, 80.8, 80.3, 80.2, 76.2, 75.4,
63.9, 28.3, 26.9, 19.1. HRM.S (TOF MS ES+): obsd 510.2297 (M+Na); calcd
510.2288.
8. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
9. Cooke, J. W. B.; Davies, S. G.; Naylor, A. Tetrahedron 1993, 49, 7955.
10. (a) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939; (b) Ibuka,
T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Ueyhara, T.; Yamamoto, Y. J.
Org. Chem. 1991, 56, 4370; (c) Sames, D.; Polt, R. J. Org. Chem. 1994, 59, 4596;
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Chattopadhyay, S. K.; Roy, S. P. Tetrahedron Lett. 2008, 49, 5498.
Compound 27: Mp: 164–166 °C. IR (KBr): 3366, 1675, 1538, 1449, 1368, 1285,
1174, 1067 cmÀ1 1H NMR (400 MHz, DMSO-d6): d 6.76 (1H, d, J = 8.4 Hz), 4.88
.
(d, 2H, J = 5.2 Hz), 4.53 (d, 2H, J = 3.2 Hz), 3.54–3.53 (m, 2H), 3.49–3.47 (m, 2H),
3.23 (q, 1H, J = 7.6 Hz), 1.38 (s, 9H). 13C NMR (100 MHz, DMSO-d6): d 155.8,
78.5, 77.4, 74.6, 61.0, 28.3. HRMS (TOF MS ES+): obsd 272.1111 (M+Na); calcd
272.1110.