Total synthesis of gabosine H

Article abstract of DOI:10.1055/s-0030-1260782

Stereoselective total synthesis and assignment of the absolute configuration of the keto carba sugar gabosine H is presented. Pivotal reactions in the sequence include desymmetrization of the dimethylamide of tartaric acid and ring-closing metathesis. Geo

Full text of DOI:10.1055/s-0030-1260782

1602
LETTER
Total Synthesis of Gabosine H
Total
S
ynthesis of
a
G
abosine
H
virayani R. Prasad,* S. Mothish Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
E-mail: prasad@orgchem.iisc.ernet.in
Received 10 February 2011
ed,4 to the best of our knowledge, preferential formation
of a monoketoamide by desymmetrization of the tartaric
acid amide with controlled addition of such Grignard
reagents has not been reported.
Abstract: Stereoselective total synthesis and assignment of the ab-
solute configuration of the keto carba sugar gabosine H is presented.
Pivotal reactions in the sequence include desymmetrization of the
dimethylamide of tartaric acid and ring-closing metathesis.
Key words: gabosine H, natural products, stereoselective synthe-
sis, ring-closing metathesis
O
OR
O
O
HO
HO
HO
HO
Me
HO
HO
Me
Gabosines are secondary metabolites comprising hydrox-
ylated branched cyclohexanone derivatives isolated from
the culture broths of a number of Streptomycetes by
Zeeck’s group.1 These compounds are also termed keto
carba sugars owing to the replacement of the ring-oxygen
atom of a cyclic monosaccharide with carbon. Hitherto,
14 gabosines have been isolated, and the absolute config-
uration of some of the gabosines has been established with
the stereochemistry of others assigned by analogy. Al-
though, gabosines do not possess any appreciable bioac-
tivity, gabosine incorporated compounds exhibit a varied
bioactive profile. This has led to the synthesis of ga-
bosines by a number of research groups. Most of the syn-
theses involve chiral pool carbohydrates or quinic acid as
the starting materials, while other asymmetric methodolo-
gies including a chemoenzymatic synthesis have also
been reported.2 Although, these reports are concerned
with the synthesis of several of the gabosines, to the best
of our knowledge no synthesis of gabosine H has been re-
ported in the literature. Gabosine H (Figure 1) was isolat-
ed from the culture broth of Streptomyces chromofuscus,
and the relative configuration was assigned by extensive
NMR experiments. As a part of our program in the synthe-
sis of natural products from tartaric acid, we report herein
the total synthesis of gabosine H and assignment of its ab-
solute stereochemistry.
OH
OH
OH
gabosine A
gabosine B
R = H, gabosine C
R = crotonyl = COTC
O
R
O
O
HO
HO
Me
HO
HO
HO
HO
OH
OH
OH
R
R = OAc = gabosine D
R = OH = gabosine E
gabosine F
R = OAc = gabosine G
R = OH = gabosine I
O
O
OH
HO
HO
HO
HO
HO
Me
HO
OH
OH OH
gabosine J
OH OAc
gabosine K
gabosine H
O
O
O
HO
HO
Me
HO
HO
Me
HO
OH
Me
HO
gabosine L
OH
OH
gabosine O
gabosine N
Figure 1 Gabosines isolated from a number of Streptomycetes
Owing to the reactivity of the resultant a,b-unsaturated
ketone as a Michael acceptor, it is challenging to synthe-
size similar monoketoamides by addition of vinylmagne-
sium bromides. However, synthesis of such a ketone
would pave the way to differently substituted cyclohex-
enols and hence the synthesis of a number of other natural
products.
Our approach to the synthesis of gabosine H is depicted in
Scheme 1. Formation of the cyclohexenone was anticipat-
ed by ring-closing metathesis of the diene 2, preparation
of which was envisaged by addition of vinylmagnesium
bromide to the g-hydroxy amide 3. Formation of the g-
hydroxy amide was proposed by desymmetrization of the
bisdimethyl amide 4 of tartaric acid involving controlled
addition of 2-propenylmagnesium bromide followed by
stereoselective reduction.3 Although, addition of vinyl-
magnesium bromide to the bis-Weinreb amide derived
from tartaric acid leading to the 1,4-diketone is document-
Accordingly, careful addition of 1.5 equivalents of 2-pro-
penylmagnesium bromide to the bisdimethylamide 4 fur-
nished the monoketoamide 5 in 84% yield.5 Reduction of
the keto group in 5 with NaBH4 in presence of CeCl3 fur-
nished the alcohol in 93% yield in 9:1 ratio.6 Careful crys-
tallization led to the isolation of the pure diastereomer 3 in
83% yield. Addition of vinylmagnesium bromide to 3 led
to the a,b-unsaturated ketone 2 in 65% yield. Ring-closing
metathesis (RCM) of 2 with Grubbs second-generation
SYNLETT 2011, No. 11, pp 1602–1604
x
x
.x
x
.2
0
1
1
Advanced online publication: 10.06.2011
DOI: 10.1055/s-0030-1260782; Art ID: D04511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Gabosine H
1603
O
O
synthesis is the formation of a g-hydroxyamide derived
from tartaric acid involving desymmetrization by con-
trolled addition of 2-propenylmagnesium bromide and
stereoselective reduction. Further application of this strat-
egy for different gabosines is under way.
HO
O
O
Me
HO
Me
OH
gabosine H
OH
2
Acknowledgment
NMe2
O
NMe2
We thank the Department of Science and Technology (DST), New
Delhi for funding of this project. KRP is a Swarnajayanthi Fellow
of DST. SMK thanks the Council of Scientific and Industrial Re-
search (CSIR), New Delhi for a research fellowship.
O
O
O
O
O
O
OH
NMe2
Me
4
3
References and Notes
Scheme 1 Retrosynthesis for gabosine H
(1) (a) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hammann, P.;
Hütter, K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Ann.
Chem. 1993, 241. (b) Tang, Y. Q.; Maul, C.; Hofs, R.;
Sattler, I.; Grabley, S.; Feng, X. Z.; Zeeck, A.; Thiericke, R.
Eur. J. Org. Chem. 2000, 149. For a review on carba sugars,
see: (c) Arjona, O.; Gómez, A. M.; Lóopez, J. C.; Plumet, J.
Chem. Rev. 2007, 107, 1919.
catalyst resulted in the cyclohexenone 6 in 62% yield.
Deprotection of the acetonide in 6 by treating with PPTS
in methanol afforded gabosine H in 92% yield
(Scheme 2). Spectroscopic data of the synthesized
gabosine H are the same as those of the natural product
reported.7 Furthermore, we confirm the absolute stere-
ochemistry of gabosine H as 2R,3S,4R based on the
specific rotation determined for our synthetic sample [a]D
–74 (c 0.6, MeOH) compared with the isolated natural
product {lit1 [a]D –68.3 (c 0.58, MeOH)}.
(2) For recent asymmetric syntheses of gabosines, see:
Gabosine F and gabosine O: (a) Shing, T. K. M.; So, K. H.;
Kwok, W. S. Org. Lett. 2009, 11, 5070 . Gabosine I and
gabosine G: (b) Shing, T. K. M.; Cheng, H. M. J. Org.
Chem. 2007, 72, 6610 . Gabosine O: (c) Carreňo, M. C.;
Merino, E.; Ribagorda, M.; Somoza, Ă.; Urbano, A. Chem.
Eur. J. 2007, 13, 1064. Gabosine N and gabosine O:
(d) Alibés, R.; Bayón, P.; de March, P.; Figueredo, M.; Font,
J.; Marjanet, G. Org. Lett. 2006, 8, 1617 . Gabosine C,
COTC gabosine C, and COTC: (e) Ramana, G. V.; Rao,
B. V. Tetrahedron Lett. 2005, 46, 3049. (f) Shinada, T.;
Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002,
1341. Gabosine A: (g) Banwell, M. G.; Bray, A. M.; Wong,
D. J. New J. Chem. 2001, 25, 1351. Racemic synthesis of
gabosine B and the putative structure of gabosine K:
(h) Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000, 41,
3509. Gabosine C and COTC: (i) Lubineau, A.; Billault, I.
J. Org. Chem. 1998, 63, 5668.
(3) For a general approach to the synthesis of g-ketoamides by
addition of alkyl or aryl Grignard reagents to tartaric acid
derived amides, see: (a) Prasad, K. R.; Chandrakumar, A.
Tetrahedron 2007, 63, 1798. For recent application of g-
keto amides derived from tartaric acid in natural product
synthesis, see: (b) Prasad, K. R.; Pawar, A. B. Synlett 2010,
1093. (c) Prasad, K. R.; Pawar, A. B. ARKIVOC 2010, (vi),
39. (d) Prasad, K. R.; Gandi, V. R.; Nidhiry, J. E.; Bhat,
K. S. Synthesis 2010, 2521. (e) Prasad, K. R.; Gandi, V. R.
Synlett 2009, 2593. (f) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2. (g) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2916. (h) Prasad, K. R.; Swain, B.
Tetrahedron: Asymmetry 2008, 19, 1134. (i) Prasad, K. R.;
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312.
(j) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643.
Me
NMe2
NMe2
O
O
O
O
MgBr
O
O
O
O
THF, –15 °C
0.5 h, 84%
NMe2
Me
4
5
NMe2
NaBH4, CeCl3
MeOH, –78 °C
O
O
MgBr
O
THF, –15 ° C
0.5 h, 65%
1.5 h, 93%
dr = 9:1
OH
Me
3
(83% after recrystallisation)
O
O
Grubbs II cat. (5 mol%)
CH2Cl2 (0.03 M), 50 °C, 6 h, 62%
Me
O
OH
2
O
O
HO
O
PPTS, MeOH
r.t., 6 h, 92%
HO
O
Me
Me
(4) For the synthesis of symmetric 1,4-diketones by addition of
vinylmagnesium bromide to tartaric acid Weinreb amide,
see: Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett.
2002, 4, 1359.
(5) Formation of minor amounts of 1,4-diketone resulting from
the addition of Grignard reagent to both amides is observed.
(6) The dr of the product alcohol was estimated to be 9:1 by
1H NMR.
OH
OH
6
gabosine H
Scheme 2 Total synthesis of gabosine H
In conclusion, a concise synthesis of gabosine H, a trihy-
droxycyclohexenone, was accomplished from tartaric
acid amide in a five-step sequence. The key reaction in the
(7) All compounds exhibited satisfactory analytical data.
Compound 5: [a]D –25.5 (c 2.6, CHCl3). IR (neat): 2989,
Synlett 2011, No. 11, 1602–1604 © Thieme Stuttgart · New York

1604
K. R. Prasad, S. M. Kumar
LETTER
2938, 1654, 1374, 1157, 1054 cm–1. 1H NMR (400 MHz,
CDCl3): d = 6.29 (s, 1 H), 6.00 (d, J = 1.0 Hz, 1 H), 5.68 (d,
J = 5.8 Hz, 1 H), 4.99 (d, J = 5.8 Hz, 1 H), 3.16 (s, 3 H), 2.98
(s, 3 H), 1.90 (s, 3 H), 1.44 (s, 3 H), 1.43 (s, 3 H). 13C NMR
(100 MHz, CDCl3): d = 197.4, 168.0, 142.3, 128.8, 112.2,
78.1, 75.1, 37.0, 35.8, 26.3, 26.2, 17.5. HRMS: m/z calcd for
C12H19NO4 + Na: 264.1212; found: 264.1205.
Compound 3: mp 74–75 °C; [a]D –26.5 (c 1.8, CHCl3). IR
(KBr): 3386, 2970, 2984, 2948, 1641, 1057, 1040, 890 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.06 (s, 1 H), 4.95 (s, 1 H),
4.82–4.79 (m, 1 H), 4.52 (d, J = 7.0 Hz, 1 H), 4.08 (dd,
J = 7.9, 3.0 Hz, 1 H), 3.13 (s, 3 H), 2.96 (s, 3 H), 2.59 (d,
J = 8.2 Hz, 1 H), 1.82 (s, 3 H), 1.46 (s, 3 H), 1.38 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.7, 144.7, 112.1, 110.6,
78.6, 74.6, 73.7, 37.0, 35.7, 26.8, 26.1, 18.8. HRMS: m/z
calcd for C12H21NO4 + Na: 266.1368; found: 266.1357.
Compound 2: [a]D +23.3 (c 1.8, CHCl3). IR (neat): 3459,
2989, 2924, 1699, 1609, 1403, 1374, 1213, 1088, 1061 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.82 (ddd, J = 17.4, 10.6,
2.4 Hz, 1 H), 6.45 (ddd, J = 17.4, 2.4, 1.5 Hz, 1 H), 5.86
(ddd, J = 17.4, 2.4, 1.5 Hz, 1 H), 5.04–4.96 (m, 2 H), 4.51–
4.49 (m, 1 H), 4.38–4.34 (m, 1 H), 4.13–4.12 (m, 1 H), 2.50–
2.48 (br s, 1 H), 1.79 (s, 3 H) 1.49 (s, 3 H) 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 198.7, 144.1, 131.5, 130.8,
113.0, 111.3, 80.8, 78.7, 74.7, 26.8, 26.0, 18.6. HRMS:
m/z calcd for C12H18O4 + Na: 249.1103; found: 249.1101.
Compound 6: mp 122–126 °C; [a]D +88.2 (c 1.0, CHCl3).
IR (KBr): 3453, 2989, 2929, 2873, 1708, 1378, 1232, 1072,
1059 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.86 (s, 1 H),
4.55 (br d, J = 7.4 Hz, 1 H), 4.09 (d, J = 10.7 Hz, 1 H), 3.85
(dd, J = 10.4, 8.4 Hz, 1 H), 3.45–3.25 (br s, 1 H), 2.07 (s, 3
H), 1.46 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 192.4,
161.3, 125.8, 113.0, 81.4, 79.7, 73.5, 26.8, 26.5, 19.5.
HRMS: m/z calcd for C10H14O4 + Na: 221.0790; found:
221.0802.
Gabosine H: mp 118–119 °C; [a]D –74.0 (c 0.6, MeOH).
IR (KBr): 3431, 2894, 2876, 1657, 1625 cm–1. 1H NMR (400
MHz, CD3OD): d = 5.92 (s, 1 H), 4.23 (d, J = 8.4 Hz, 1 H),
4.01 (d, J = 10.8 Hz, 1 H), 3.56 (dd, J = 10.8, 2.4 Hz, 1 H),
2.07 (s, 3 H). 13C NMR (100 MHz, CD3OD): d = 199.4,
165.7, 125.0, 79.1, 78.0, 75.1, 20.0. HRMS: m/z calcd for
C7H10O4 + Na: 181.0477; found: 181.0477.
Synlett 2011, No. 11, 1602–1604 © Thieme Stuttgart · New York