First total syntheses of (+)-garvensintriol and (+)-5- epi -garvensintriol

Article abstract of DOI:10.1055/s-0029-1219557

A concise and efficient carbohydrate-based approach for the total syntheses of (+)-garvensintriol and (+)-5-epi-garvensintriol is described in nine and six steps with 20% and 37% overall yield, respectively, starting from a known intermediate. A sequence of Grignard-assisted lactol opening with terminal alkyne, stereoselective keto reduction and oxidative lactonization are the key reactions. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219557

LETTER
1059
First Total Syntheses of (+)-Garvensintriol and (+)-5-epi-Garvensintriol
First
Total
S
ynthes
e
es of (+)-G
b
arvensintriol
e
and (+)-5-
n
epi-Garvensi
d
ntriol ra K. Mohapatra,* B. Prem Kumar, K. Bhaskar, Jhillu S. Yadav*
Organic Chemistry Division I, Indian Institute of Chemical Technology (CSIR), Uppal Road, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: mohapatra@iict.res.in
Received 24 December 2009
The absolute configuration was assigned as
(5S,6R,7S,8S), which was different from that of (+)-
Abstract: A concise and efficient carbohydrate-based approach for
the total syntheses of (+)-garvensintriol and (+)-5-epi-garvensintri-
ol is described in nine and six steps with 20% and 37% overall yield,
respectively, starting from a known intermediate. A sequence of
goniotriol
(4),
whose
absolute
configuration
(5S,6R,7R,8R) was previously determined by X-ray crys-
Grignard-assisted lactol opening with terminal alkyne, stereoselec- tallographic analysis.6 Because of the wide distribution of
tive keto reduction and oxidative lactonization are the key reactions.
the styryl lactone class of natural products in nature with
interesting biological activities and to confirm the struc-
ture and configuration, we have taken up the synthesis of
(+)-garvensintriol (1) and (+)-5-epi-garvensintriol (2).
Keywords: garvensintriol, goniotriol, cytotoxic, oxidative lacton-
ization, Grignard-assisted lactol opening
The retrosynthetic analysis of our approach is shown in
Scheme 1. It was envisioned that (+)-garvensintriol (1)
and (+)-5-epi-garvensintriol (2) could be obtained from D-
(–)-ribose. The six-membered lactone could be construct-
ed by oxidative lactonization of triol 8. The triol 8 could
be obtained from keto derivative 13. The crucial interme-
diate 9 could be obtained from a Grignard-assisted open-
ing of a known lactol 11 with a terminal alkyne 10.
Lactone rings are a structural feature of simple to highly
complex biologically active natural products.1 Among
them, six-membered lactone moieties are relatively com-
mon in various types of natural sources.2 These natural
and designed molecules possess cytotoxic, anti-HIV, apo-
ptosis induction, antileukemic activity and other relevant
pharmacological properties.3 Several bioactive styryl lac-
tones have been reported from goniothalamus species
which are found to possess significant cytotoxic activity
against several human tumor cell lines.4 (+)-Garvensintri-
ol (1) was isolated from the methanolic extract of G.
arvensis stem bark along with (+)-altholactone (3), (+)-
goniotriol (4), (+)-etharvendiol (5) and (+)-goniofufurone
(6; Figure 1).5 The structure of (+)-garvensintriol (1) was
determined from IR, 1H NMR, 13C NMR and mass spec-
tral analysis.
OH
OH
OH
OH
O
O
Ph
O
O
Ph
OH
OH
1
2
OH
OH OBn
Ph
OBn
HO
HO
Ph
+
OH
OBn OH
OBn
OH
OH
OH
OH
7
8
O
O
Ph
O
O
Ph
OH
OH
OH
O
(+)-5-epi-garvensintriol (2)
(+)-garvensintriol (1)
Ph
THPO
H
O
OH
OH
O
OH
9
Ph
O
O
Ph
O
O
OTHP
HO
OH
(+)-goniotriol (4)
OH
10
Ph
(+)-altholactone (3)
O
HO
O
OEt
OH
D-(–)-ribose
O
O
O
O
O
O
Ph
OH
OH
(+)-etharvendiol (5)
11
(+)-goniofurfurone (6)
Scheme 1 Retrosynthetic analysis of (+)-garvensintriol (1) and (+)-
5-epi-garvensintriol (2)
Figure 1 Structures of few novel styryl lactones
The synthesis of the key intermediate 11 was obtained
from D-(–)-ribose following a known protocol.7 The lactol
ring opening with in situ metalated alkyne (obtained by
treating 10 with ethyl magnesium bromide) afforded the
SYNLETT 2010, No. 7, pp 1059–1062
Advanced online publication: 26.02.2010
DOI: 10.1055/s-0029-1219557; Art ID: G37809ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

1060
D. K. Mohapatra et al.
LETTER
OH
OH
O
HO
Ph
ref. 7
a
b
THPO
Ph
D-(–)-ribose
OTHP
O
O
O
O
O
10
11
9
OBn
OH
OH
e
c, d
THPO
THPO
Ph
Ph
O
O
O
O
13
f
O
12
OBn
Ph
OBn
O
OBn
Ph
OH
OBn
Ph
OH
g
THPO
THPO
THPO
+
O
O
O
O
16
14
15
OH
OH OBn
Ph
OBn
OBn
OH
h
i
HO
O
O
Ph
O
O
Ph
OH
OBn
OH
OH
5-epi-garvensintriol (2)
8
17
Scheme 2 Reagents and conditions: (a) EtMgBr, THF, 6, 0 °C to r.t., 6 h, 80%; (b) Pd/C, H2, EtOAc, 4 h, 91%; (c) NaH, BnBr, DMF, 0 °C
to r.t., 2 h, 90%; (d) PDC, CH2Cl2, r.t., 85%; (e) (S)-CBS, BH3·Me2S, THF, –100 °C, 4 h, 82%; (f) NaH, BnBr, DMF, 0 °C to r.t., 2 h, 84%; (g)
p-TSA, MeOH, r.t., 6 h, 89%; (h) TEMPO, BAIB, CH2Cl2, 0 °C to r.t., 4 h, 87%; (i) TiCl4, CH2Cl2, r.t., 2 h, 76%
anti isomer as the only product in 80% yield.8 The initial Out of all the reagents tried, reduction using (S)-2-methyl-
attempt for inversion of secondary hydroxyl center fol- CBS-oxazaborolidine11 afforded the required hydroxyl
lowing Mitsunobu protocol9 was not successful. At this compound 14 and its epimer 15 in a ratio of 9:1
juncture, proceeding further with compound 9 led to the (Scheme 2). Both the isomers were separated by silica gel
(+)-5-epi-garvensintriol (2) in five steps. To obtain both column chromatography and characterized separately.
(+)-garvensintriol (1) and (+)-5-epi-garvensintriol (2),
compound 9 was treated with Pd/C under hydrogen atmo-
sphere to obtain the saturated product 12 in 91% yield.
The selective protection of the benzyl alcohol with NaH
To obtain (+)-5-epi-garvensintriol (2), compound 12 was
benzylated with NaH and benzyl bromide to afford the
dibenzyl derivative 16 in 86% yield. Dibenzyl derivative
16 was also obtained by treating compound 15 with NaH
and benzyl bromide followed by oxidation with pyridini-
and benzyl bromide in 84% yield. Both acetonide and
um dichromate (PDC)10 reagent in CH2Cl2 resulted in keto
THP group deprotection with p-TSA in methanol afforded
derivative 13 in 77% yield over two steps. The selective
the triol 812 in 89% yield. The oxidation of the triol 8 in
reduction under different reaction conditions (Table 1)
the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
was studied at this stage to obtain the required syn isomer.
(TEMPO) and [bis(acetoxy)iodo]benzene (BAIB) pro-
duced the six-membered lactone 1713 in 87% yield.14 Fi-
nally, deprotection of the benzyl groups with excess TiCl4
Table 1 Results of Selective Reduction
in CH2Cl2 at room temperature afforded the (+)-5-epi-
garvensintriol (2)15 in 76% yield.16
Entry Reducing agents Conditions
14/15 Yield (%)a
The assigned structure of (+)-5-epi-garvensintriol (2) was
1
2
3
4
5
6
7
NaBH4
MeOH, 0 °C, 30 min 1:9 89
1
confirmed by IR, H NMR, 13C NMR and mass spectral
L-Selectride
NaB(OAc)3H
NaBH4–CeCl3
(R)-CBS
THF, –78 °C, 4 h
THF, –78 °C, 2 h
1:4 85
1:4 90
analysis. The product after purification and recrystalliza-
tion produced single crystals whose X-ray analysis further
confirmed its structure and absolute configuration to be
(5S,6R,7S,8S).17
MeOH, –100 °C, 4 h 2:3 84
After the synthesis of (+)-5-epi-garvensintriol (2) and
confirmation of its absolute configuration by X-ray crys-
tallographic analysis, the synthesis of the natural product
1 was initiated. Starting from intermediate 14 and follow-
ing the same sequence of reactions18,19 as followed for
compound 15 to (+)-5-epi-garvensintriol (2), the total
THF, –78 °C, 4 h
THF, –78 °C, 4 h
THF, –78 °C, 3 h
1:9 85
9:1 82
1:9 80
(S)-CBS
ZnBH4
a Isolated yield.
Synlett 2010, No. 7, 1059–1062 © Thieme Stuttgart · New York

LETTER
First Total Syntheses of (+)-Garvensintriol and (+)-5-epi-Garvensintriol
1061
OBn
Ph
OBn
OH
OBn
Ph
b
a
THPO
THPO
O
O
O
O
14
18
OH
OH
OBn
OBn
OH OBn
Ph
c
d
OH
HO
O
O
Ph
O
O
Ph
OH
OBn
OH
7
19
garvensintriol (1)
Scheme 3 Reagents and conditions: (a) NaH, BnBr, DMF, 0 °C to r.t., 4 h, 80%; (b) p-TSA, MeOH, r.t., 6 h, 87%; (c) TEMPO, BAIB, CH2Cl2,
0 °C to r.t., 4 h, 85%; (d) TiCl4, CH2Cl2, r.t., 2 h, 74%.
synthesis of (+)-garvensintriol (1)20 was achieved in four
steps (Scheme 3).
(4) (a) Fang, X. P.; Anderson, J. E.; Qui, X. X.; Kozlowski, J. F.;
Chang, C. J.; McLaughlin, J. L. Tetrahedron 1993, 49,
1563. (b) Goh, S. H.; Ee, G. C. L.; Chuah, C. H. Nat. Prod.
Lett. 1995, 5, 255. (c) McLaughlin, J. L.; Chang, C. J.;
Smith, D. L. In Human Medicinal Agents from Plants;
Kinghorn, A. D.; Baladrin, A., Eds.; American Chemical
Society: Washington, 1993, Vol. 534, 112.
The spectral data were in good agreement with those of
the natural product but the analytical value showed a dif-
25
25
ference {[a]D +70.3 (c = 1.5, EtOH); lit.5 [a]D +7.8
(c = 3.3, EtOH)} which might be due to typographical er-
ror.
(5) Bermejo, A.; Blázquez, M. A.; Rao, K. S.; Cortes, D.
Phytochemistry 1998, 47, 135.
In conclusion, we have succeeded in the concise stereose-
lective syntheses of (+)-garvensintriol (1) and (+)-5-epi-
garvensintriol (2) from a known lactol 11 in nine and six
steps with 20% and 37% overall yield, respectively. The
absolute configurations of (+)-garvensintriol (1) and (+)-
5-epi-garvensintriol (2) have been elucidated. Following
the same protocol, other related natural products synthe-
ses are in progress and will reported in due course.
(6) Alkofahi, A.; Ma, W. W.; McKenzie, A. T.; Byrn, S. R.;
McLaughlin, J. L. J. Nat. Prod. 1989, 52, 1371.
(7) Koeski, K.; Ebata, T.; Matsushita, H. Biosci. Biotech.
Biochem. 1996, 60, 534.
(8) Rycroft, A. D.; Singh, G.; Wightman, R. H. J. Chem. Soc.,
Perkin Trans. 1 1995, 1667.
(9) Mitsunobu, O. Synthesis 1981, 1.
(10) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
(11) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.;
Chen, C. P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109,
7925. (c) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763.
(d) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
(12) Analytical and Spectral Data of 8: white solid; mp 67 °C;
[a]D25 +48.0 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.15–7.62 (m, 15 H), 4.60 (d, J = 6.0 Hz, 1 H), 4.46 (d,
J = 13.6 Hz, 3 H), 4.29 (d, J = 11.3 Hz, 1 H), 3.96 (dd, J =
7.6, 2.7 Hz, 1 H), 3.48–3.72 (m, 4 H), 3.23 (br s, 1 H), 2.96
(br s, 1 H), 1.89 (br s, 1 H), 1.50–1.81 (m, 4 H). 13C NMR
(75 MHz, CDCl3): d = 137.9, 137.5, 137.5, 128.4, 128.3,
128.2, 128.0, 127.9, 127.7, 83.2, 80.3, 74.3, 71.7, 71.5, 70.7,
62.6, 28.2, 24.9. MS (ESI): m/z = 437 [M + H]+.
(13) Analytical and Spectral Data of 17: white solid; mp 139
°C; [a]D25 = –22.2 (c = 1.5, CHCl3). IR (neat): 3395, 3029,
2960, 2911, 2859, 1746, 1453, 1396, 1259, 1086, 1028, 761,
705 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.17–7.51 (m, 15
H), 4.31–4.59 (m, 5 H), 4.19 (d, J = 11.3 Hz, 1 H), 3.99–4.12
(m, 2 H), 2.56–2.79 (m, 1 H), 2.19–2.55 (m, 2 H), 1.93–2.16
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 171.2, 137.7,
137.2, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7,
127.7, 81.8, 81.0, 74.4, 70.7, 70.5, 69.7, 26.0, 22.7. MS
(ESI): m/z = 455 [M + Na]+.
(14) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.;
Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
(15) Analytical and Spectral Data of 2: white solid; mp 163 °C;
[a]D25 –10.1 (c = 0.5, EtOH). IR (neat): 3533, 3346, 2923,
1773, 1200, 1083, 1026, 897, 850, 705, 673 cm–1. 1H NMR
(300 MHz, CD3OD): d = 7.07–7.51 (m, 5 H), 4.77 (m, 2 H),
4.60 (br s, 3 H), 3.65–3.78 (m, 2 H), 2.09–2.62 (m, 4 H). 1H
NMR (300 MHz, DMSO-d6): d = 7.12–7.53 (m, 5 H), 5.35
Acknowledgment
B.P.K. and K.B. thank the Council of Scientific & Industrial re-
search (CSIR), New Delhi, for the financial assistance in the form
of research fellowships. D.K.M. thanks the CSIR for a research
grant (INSA Young Scientist Award). We are thankful to Dr. B.
Sridhar for his help for X-ray crystallographic analysis.
References and Notes
(1) (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed.
1985, 24, 94. (b) Negishi, E.; Kotora, M. Tetrahedron Lett.
1997, 53, 6707. (c) Collins, I. J. Chem. Soc., Perkin Trans. 1
1999, 1377. (d) Carter, N. B.; Nadany, A. E.; Sweeney, J. B.
J. Chem. Soc., Perkin Trans. 1 2002, 2324.
(2) (a) Davis-Coleman, M. T.; Rivett, D. E. A. Prog. Chem.
Org. Nat. Prod. 1989, 55, 1. (b) Dickinson, J. M. Nat. Prod.
Rep. 1993, 10, 71. (c) Collett, L. A.; Davies-Coleman, M.
T.; Rivette, D. E. A. Prog. Chem. Org. Nat. Prod. 1998, 75,
181.
(3) (a) Chrusciel, R. A.; Strohbach, J. W. Curr. Top. Med.
Chem. 2004, 4, 1097; and references therein. (b) Chan,
K. M.; Rajab, N. F.; Ishak, N. H. A.; Ali, A. M.; Yusoff, K.;
Din, L. B.; Inayat-Hussain, S. H. Chem.-Biol. Interact. 2006,
159, 129; and references therein. (c) Newmeyer, D. D.;
Ferguson-Miller, S. Cell 2003, 112, 481; and references
therein. (d) Kikuchi, H.; Sasaki, K.; Sekiya, J.; Maeda, Y.;
Amagai, A.; Kubohara, Y.; Ohsima, Y. Bioorg. Med. Chem.
2004, 12, 3203. (e) Richetti, A.; Fimiani, V.
Immunopharmacol. Immunotoxicol. 2003, 25, 441.
Synlett 2010, No. 7, 1059–1062 © Thieme Stuttgart · New York

1062
D. K. Mohapatra et al.
LETTER
(dd, J = 13.8, 3.8 Hz, 2 H), 4.84 (d, J = 4.9 Hz, 1 H), 4.71 (s,
2 H), 3.44–3.66 (m, 2 H), 1.95–2.48 (m, 4 H). 13C NMR (75
MHz, CD3OD): d = 180.8, 142.2, 129.9, 128.9, 128.6, 83.1,
76.4, 75.3, 73.4, 29.8, 21.8. MS (ESI): m/z = 275 [M + Na]+.
(19) Analytical and Spectral Data of 19: white solid; mp 127
°C; [a]D25 = +3.2 (c = 0.5, CHCl3). IR (neat): 3464, 3030,
2923, 1736, 1494, 1452, 1354, 1239, 1201, 1090, 1055, 741,
700, 579 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.20–7.54
(m, 15 H), 4.75 (d, J = 3.6 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1
H), 4.41–4.55 (m, 3 H), 4.31 (d, J = 11.3 Hz, 1 H), 3.95 (br
s, 1 H), 3.74 (dd, J = 8.7, 1.5 Hz, 1 H), 2.58–2.76 (m, 1 H),
2.88 (br s, 1 H), 2.35–2.56 (m, 1 H), 2.78–2.15 (m, 1 H),
1.57–1.78 (m, 1 H). 13C NMR (75 MHz, CDCl3): d = 169.9,
137.7, 137.5, 136.3, 128.4, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 80.7, 80.5, 71.3, 71.1, 71.0, 68.2, 25.4, 23.0.
MS (ESI): m/z = 455 [M + Na]+.
(16) (a) Corey, E. J.; Gras, J. L.; Ulrisch, P. Tetrahedron Lett.
1976, 809. (b) Bhatt, M. V.; Kulkarni, S. V. Synthesis 1983,
249.
(17) Crystallographic data for the structure in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC 755246
for 17. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK [fax: +44 (1223)336033 or e-mail:
(20) Analytical and Spectral Data of 1: [a]D25 +70.3 (c = 1.5,
MeOH). IR (neat): 3396, 2921, 1756, 1453, 1371, 1270,
1195, 1079, 1043, 917, 815, 705, 578 cm–1. 1H NMR (300
MHz, CDCl3): d = 7.28–7.51 (m, 5 H), 4.95 (t, J = 6.2 Hz, 1
H), 4.85 (d, J = 6.6 Hz, 1 H), 3.93 (t, J = 7.6 Hz, 1 H), 3.59
(dd, J = 7.9, 1.3 Hz, 1 H), 2.58–2.75 (m, 1 H), 2.39–2.56 (m,
1 H), 2.14–2.38 (m, 2 H), 1.71 (br s, 2 H). 13C NMR (75
MHz, CD3OD): d = 180.9, 142.2, 128.6, 128.9, 129.1, 81.3,
76.6, 75.6, 74.4, 29.5, 24.4. MS (ESI): m/z = 253 [M + H]+.
deposit@ccdc.cam.ac.uk].
(18) Analytical and Spectral Data of 7: white solid; mp 93 °C;
[a]D25 +26.4 (c = 1.5, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 7.17–7.50 (m, 15 H), 4.40–4.64 (m, 4 H), 4.24 (d, J =
11.5 Hz, 1 H), 3.99 (t, J = 5.7 Hz, 1 H), 3.75 (t, J = 5.5 Hz,
1 H), 3.48 (t, J = 6.0 Hz, 2 H), 3.38 (d, J = 7.6 Hz, 1 H), 2.90
(br s, 3 H), 1.61–1.74 (m, 2 H), 1.38–1.52 (m, 2 H). 13
C
NMR (75 MHz, CDCl3): d = 137.9, 137.6, 137.5, 128.4,
128.3, 128.2, 128.0, 127.8, 82.6, 78.3, 74.3, 72.3, 72.0, 70.6,
62.5, 28.5, 26.5. MS (ESI): m/z = 437 [M + H]+.
Synlett 2010, No. 7, 1059–1062 © Thieme Stuttgart · New York

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