Use of nitriles in synthesis. First total synthesis of ent-sachalinol A

Article abstract of DOI:10.1055/s-2006-944223

The total synthesis of ent-sachalinol A, has been achieved by utilizing a Sharpless epoxidation and nitrile substitution as the key reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944223

LETTER
1715
Use of Nitriles in Synthesis. First Total Synthesis of ent-Sachalinol A
Total
S
ynthesis of
a
ent-Sachali
v
nol
A
id Díez,* Marta G. Nuñez, R. F. Moro, A. B. Antón, N. M. Garrido, I. S. Marcos, P. Basabe
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1–5, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: ddm@usal.es
Received 13 February 2006
Dedicated with respect and affection to Prof. J. G. Urones on the occasion of his 65th birthday.
Abstract: The total synthesis of ent-sachalinol A, has been
achieved by utilizing a Sharpless epoxidation and nitrile substitu-
tion as the key reactions.
OTHP
Ref. 3
O
OH
OTHP
OTHP
Key words: sachalinol A, Sharpless epoxidation, nitriles, mono-
terpenes
a
O
O
b
OTs
OH
Recently Kadota et al. described the isolation of Sachali-
nols A–C, from Rhodiola Sachalinensis,1 as new mono-
terpenoids. Rosiridin, the glucoside of Sachalinol A,
which was previously isolated from Rhodiola Rosea,2 and
exhibited non-competitive endopeptidase inhibition
against Flavobacterium PEP with an IC50 of 84 mM
(Figure 1).
OTHP
1
Scheme 1 Reagents and conditions: a) L-(+)-DET, Ti(i-PrO)4,
TBHP, CH2Cl2, –23 °C (63%); b) TsCl, py, 0 °C, (92%).3
dehydration of oximes.6 We have experience in epoxide-
opening to give allylic alcohols,7 so we decided to treat
epoxide 1, obtained as a single enantiomer by Sharpless
epoxidation (ee >97%, Scheme 1), with NaCN in
HMPA,8 (Scheme 2) followed by deprotection of the tet-
rahydropyranyl group with p-TsOH in MeOH. This gave
the a,b-unsaturated nitrile 2,9 which has the chiral alcohol
and the olefin with the E configuration (Scheme 2).5 First-
ly, we decided to carry out the synthetic sequence with the
hydroxy group of 2 unprotected. Reduction of the nitrile
group was carried out with DIBAL in two steps.10 The
first reduction gave aldehyde 4, although in low yield
(35%), and a second DIBAL reduction gave triol 6 in 40%
yield. The spectroscopic properties of 6 were in agree-
ment with those reported for sachalinol A1 except for the
specific rotation being [a]D20 –17.1 (c 0.17, MeOH) for
the natural compound and [a]D20 –2.0 (c 1.0, MeOH),
[a]D20 –7.4 (c 0.19, MeOH) for 6. In order to check the
enantiomeric excess of 6, the Mosher diester with (S)-(+)-
a-methoxy-a-trifluoromethylphenylacetyl chloride (10
equivalents) was obtained,11 giving only one compound
by NMR with a specific rotation of [a]D20 –48.0 (c 1.1,
CHCl3).
OH
OH
OH
OH
OGlc
OH
Sachalinol A
OH
Rosiridin
OH
O
O
HO
HO
Sachalinol B
Sachalinol C
Figure 1
Continuing our studies on iodine cyclization for the syn-
thesis of 2,2,6,6-tetrasubstituted tetrahydropyrans, we
have described a straightforward synthesis of epoxide 1,
starting from acetone and propargyl alcohol (Scheme 1).3
The synthesis of ent-sachalinol A from this tosylepoxide
would require the addition of one extra carbon, epoxide-
opening, and establishment of the olefin with E stereo-
chemistry. Nitrile chemistry could answer these three
questions.
Nitriles4 and a,b-unsaturated nitriles5 are very useful com-
pounds in organic synthesis. There are several methods
for the synthesis of the latter, including: alkenation of
aldehydes, displacement of halides from vinyl halides by
cyanide ion, transformation of a,b-alkylenenitriles, or
Thus, compound 6 was established as ent-sachalinol A
and in this manner we have corroborated the structure and
stereochemistry of the natural sachalinol A. The differ-
ence in the specific rotation of the natural compound
sachalinol A and 6 could be understood in terms of the low
concentration used for the measurement of the natural
product. In order to obtain 6 in better yield, alcohol 2 was
protected as its TBDMS derivative 3 under the usual con-
ditions.12 Double DIBAL reduction as before and final
TBAF deprotection13 gave ent-sachalinol in 37% overall
yield (from epoxide 1).
SYNLETT 2006, No. 11, pp 1715–1716
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944223; Art ID: D04506ST
© Georg Thieme Verlag Stuttgart · New York

1716
D. Díez et al.
LETTER
Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333.
(d) Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org.
Lett. 2004, 6, 3917. (e) Yadav, J. S.; Reddy, B. V. S.; Basak,
A. K.; Visali, B.; Narsaiah, A. V.; Nagaiah, K. Eur. J. Org.
Chem. 2004, 546.
The use of the enantiomer of epoxide 1 obtained by
Sharpless epoxidation with D-(–)-DET will lead to the
correct stereochemistry for sachalinol A.
In conclusion, we have developed an easy procedure for
the synthesis of sachalinol A and its enantiomer.
(6) (a) Mori, N.; Togo, H. Synlett 2005, 1456; and references
cited therein. (b) Fleming, F. F.; Zhang, Z. Tetrahedron
2005, 61, 747. (c) Movassagh, B.; Shokri, S. Tetrahedron
Lett. 2005, 46, 6923.
(7) Diez, D.; Marcos, I. S.; Basabe, P.; Romero, R. E.; Moro, R.
F.; Lumeras, W.; Rodriguez, L.; Urones, J. G. Synthesis
2001, 1013.
O
OTs
OTHP
a
1
(8) Wright, J. N.; Calder, M. R.; Akhtar, M. J. Chem. Soc.,
Chem. Commun. 1985, 1733.
OR
OR
OR
c
d
(9) (2E,4S)-4,7-Dihydroxy-3,7-dimethyloct-2-enenitrile (2):
NaCN (605 mg, 12.36 mmol) was added to a solution of 1
(1.7 g, 4.12 mmol) in HMPA (8 mL). After stirring for 3 h,
the mixture was diluted with H2O (150 mL). The aqueous
layer was extracted with EtOAc (5 × 100 mL) and the
combined organic extracts were washed with 10% aq HCl
(3 × 50 mL), 5% aq NaHCO3 (3 × 50 mL), and brine (3 × 50
mL). The aqueous acidic layer was extracted with EtOAc
(100 mL) and the combined organic extracts washed again
with 5% aq NaHCO3 (3 × 10 mL) and brine (3 × 10 mL).
The organic solution was dried and the filtrate was
concentrated to give 1.6 g of the crude product, which was
dissolved in MeOH (20 mL). Then, a catalytic amount of
p-TsOH (75 mg, 0.41 mmol) was added and, after stirring for
2 h, the reaction was quenched by the addition of NaHCO3
(100 mg). The MeOH was evaporated and the mixture was
dissolved in EtOAc, filtered, and concentrated to give nitrile
2 (605 mg, 80%), which was used in the next step without
further purification; [a]D20 –27.0 (c 2.0, CHCl3). IR (film):
3400 (br), 2970–2870, 2222, 1632, 1441, 1381, 1215, 1152,
1090, 910 cm–1. 1H NMR (200 MHz, CDCl3): d = 5.55 (1 H,
s, H-2), 4.18 (1 H, m, H-4), 2.01 (3 H, s, H-10), 1.9–1.2 (4
H, m, H-5, H-6), 1.24 (6 H, s, H-8, H-9). 13C NMR (100
MHz, CDCl3): d = 17.71 (C-10), 29.35 (C-5), 29.53 (C-9),
29.57 (C-8), 38.36 (C-6), 70.76 (C-7), 74.43 (C-4), 94.95 (C-
2), 117.27 (C-1), 166.07 (C-3). HRMS-EI: m/z calcd for
C10H17O2N [M]+: 183.1259; found: 183.1237.
OR
OR
OR
CN
CHO
CH2OH
R =
2 H
R =
4 H
R =
6 H
e
b
3 TBDMS
5 TBDMS
7 TBDMS
Scheme 2 Reagents and conditions: a) NaCN, HMPA, r.t., then
p-TsOH, MeOH, r.t. (80%); b) TBDMSOTf, 2,6-Lutidine, THF, r.t.
(85%); c) DIBAL (1 equiv), –78 °C, CH2Cl2; 2 to 4 (35%), 3 to 5
(85%); d) DIBAL (1 equiv), –78 °C, CH2Cl2; 4 to 6 (35%), 5 to 7
(65%); e) TBAF, THF (75%).
Acknowledgment
Financial support for this work came from the Spanish MEC
(CTQ2005-06813/BQU) and Junta de Castilla y León (Spain)
(SA045A05). The authors also thank Dr. A. M. Lithgow for the
NMR spectra and Dr. César Raposo for the MS. M. G. N. is grateful
for a FPU doctoral fellowship from the Spanish MEC.
References and Notes
(1) Fan, W.; Tezuka, Y.; Ni, K. M.; Kadota, S. Chem. Pharm.
Bull. 2001, 49, 396.
(2) Kurkin, V. A.; Zapesochnaya, G. G.; Shchavinskii, A. N.
Khim. Prir. Soedin. 1985, 21, 632; Chem. Abstr. 1986, 104,
102314p.
(3) Diez, D.; Moro, R. F.; Lumeras, W.; Rodriguez, L.; Marcos,
I. S.; Basabe, P.; Escarcena, R.; Urones, J. G. Synlett 2001,
1335.
(4) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1.
(5) (a) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.
For unsaturated nitriles, see also: (b) Fleming, F. F.;
Gudipati, V.; Steward, O. W. Tetrahedron 2003, 59, 5585.
(c) Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.;
(10) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443.
(11) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
34, 2543.
(12) Kocienski, P. J. In Protecting Groups; George Thieme
Verlag: Stuttgart, 1994.
(13) Nicolau, K. C.; Xu, J. Y.; Kim, S.; Pfefferkorn, J.; Ohshima,
T.; Vourloumis, D.; Hosokawa, S. J. Am. Chem. Soc. 1998,
120, 8661.
Synlett 2006, No. 11, 1715–1716 © Thieme Stuttgart · New York