The first total synthesis of sequosempervirin A through an orthoester Claisen rearrangement-ring closing metathesis sequence

Article abstract of DOI:10.1016/j.tetlet.2007.03.084

The first total synthesis of sequosempervirin A, a norlignan with a unique spirocyclic structure has been accomplished using an orthoester Claisen rearrangement-ring closing metathesis sequence.

Full text of DOI:10.1016/j.tetlet.2007.03.084

Tetrahedron Letters 48 (2007) 3355–3358
The first total synthesis of sequosempervirin A through
an orthoester Claisen rearrangement—ring closing
metathesis sequence
Soumitra Maity and Subrata Ghosh*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 15 February 2007; revised 8 March 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—The first total synthesis of sequosempervirin A, a norlignan with a unique spirocyclic structure has been accomplished
using an orthoester Claisen rearrangement—ring closing metathesis sequence.
Ó 2007 Elsevier Ltd. All rights reserved.
Sequosempervirin A 1 is the first naturally occurring
norlignan possessing an unusual [4.5] decane ring sys-
tem. It was isolated1 from Sequoia sempervirens, a spe-
cies of the taxodiaceae family. A variety of compounds
such as terpenoids,2 lignans3 and flavonones4 have
earlier been isolated from taxodiaceae. Some of these
compounds showed antifungal,5 antibacterial6 and
antitumour7 activity. Thus, sequosempervirin A is also
expected to exhibit useful bioactivity, however, as yet,
none has been reported. We initiated a program to de-
velop a flexible strategy for the synthesis of this structur-
ally unique compound and its structural analogues in
order to evaluate their biological activities. We herein
report the first total synthesis of sequosempervirin A.
X
OH
Ar
2
1
HO
X
X
OH
CO2Et
4
3
Scheme 1.
The key step in our strategy is the synthesis of the spiro-
cycle through ring closing metathesis (RCM)8 of diene 2
prepared from an appropriately substituted cyclohexane
derivative. Diene 2 may be available by elaboration of
cyclohexane derivative 3, which in turn should be avail-
able from orthoester Claisen rearrangement of allyl
alcohol 4 (Scheme 1).
2).10 Lithium aluminum hydride reduction of ester 6 at
rt produced alcohol 7 in 86% yield. Orthoester Claisen
rearrangement of allylic alcohol 7 was achieved at
140 °C to produce the unsaturated ester 8. Alkylation
of the lithium enolate generated from ester 8 with p-
methoxybenzyl bromide afforded ester 9 in excellent
yield. Ester 9 was then transformed into aldehyde 10
through a sequence of reduction (LiAlH4) and Swern
oxidation. The addition of vinyl magnesium bromide
to aldehyde 10 gave a single diastereomer of the dienol
Our initial target was to generate a diene analogous to
structure 2. The synthesis began with Horner–Wads-
worth–Emmons olefination of the cyclohexanone deriv-
ative 59 with triethyl phosphonoacetate (TEPA) to
produce the unsaturated ester 6 in 84% yield (Scheme
1
12 in 80% yield as revealed by H and 13C NMR spec-
troscopy. The stereochemical assignment of dienol 12
follows from addition of vinyl magnesium bromide to
the carbonyl group using Cram’s model. For removal
of the hydroxyl group we explored the possibility of
radical induced cleavage of xanthate 13. Surprisingly,
Keywords: Lignans; Metathesis; Rearrangement; Spiro compounds.
*
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473
2805; e-mail: ocsg@iacs.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.084

3356
S. Maity, S. Ghosh / Tetrahedron Letters 48 (2007) 3355–3358
R1 R2
R1 R2
ile rearrangement of xanthate 13 even at 0 °C may be
i, ii
attributed to relief of the strain arising from steric
crowding in the vicinity of the reacting centre. Facilita-
tion of the [3.3] rearrangement of the allyl xanthate by
steric buttressing, as observed here, is unprecedented.
O
R3
5
6, R3 = COOEt
7, R3 = CH2OH
We then decided to reverse the sequence, that is, first to
carry out the RCM of dienol 12 then reductive removal
of the hydroxyl group. RCM of dienes possessing sec-
ondary hydroxyl groups at the allylic position with
Ru-carbene has often been reported to follow non-met-
athetic processes12 involving isomerisation of double
bonds. Fortunately, RCM of dienol 12 with Grubbs
1st generation catalyst13 (PCy3)2Cl2Ru@CHPh 11,
(4 mol %) proceeded smoothly to give exclusively, spiro-
cycle 16 in 81% yield. The cis-orientation of the hydro-
xyl and p-methoxy benzyl groups in spirocycle 16 was
indicated by the coupling constant (J = 6.3 Hz) of the
proton adjacent to the hydroxyl group14 thus confirming
the stereochemical assignment of dienol 12. This stereo-
chemical assignment was further confirmed by a positive
NOE (1.4%) observed between the proton adjacent to
the OH group and the proton adjacent to the benzyl
group in cyclopentenol 16. TBTH reduction of xanthate
17, prepared from spirocyclopentenol 16, led to an
inseparable mixture of isomeric cyclopentenes 18 and
19 (2:1) in excellent yield. The structures of the cyclo-
pentenes were established by transformation of the mix-
ture of 18 and 19 to sequosempervirin A 1 and iso-
sequosempervirin A 26, respectively, as follows. Treat-
ment of the mixture with 3 N HCl effected deketaliza-
tion to produce a mixture of isomeric cyclopentenes 20
and 21. Reduction of this mixture of ketones afforded
four diastereoisomeric alcohols 22, 23, 24 and 25. Chro-
matography of this mixture afforded two fractions. The
minor fraction (Rf = 0.5) (ethyl acetate–petroleum
ether) obtained in 34% yield was demethylated15 with
sodium ethanethiolate to produce a mixture of the reg-
ioisomeric cyclopentene derivatives which on flash chro-
matography (silica gel 230–400 mesh) afforded
sequosempervirin A 1 in 50% yield and iso-sequosem-
pervirin A 26 (23%). Sequosempervirin A 1 prepared
in this way had mp 169–170 °C (lit.1 172–174 °C). The
1H and 13C NMR spectral data of the synthetic sample
were closely comparable to those reported in the litera-
ture.1 Thus, the minor fraction obtained from reduction
of ketones 20 and 21 was a mixture of the regioisomeric
cyclopentenes 24 and 25 (Scheme 3).
iii, iv
R1 R2
R1 R2
v
R3
R3
O
H
O
OEt
10, R3 =
p
-MeOC6H4CH2 8, R3 = H
9, R3 =
p-MeOC6H4CH2
vi
R1 R2
R1 R2
R3
vii
R3
O
H
H
HO
MeS
S
12, R3 =
p
-MeOC6H4CH2
13, R3 =
p-MeOC6H4CH2
R1 R2
R3
R4
14, R3 =
p
-MeOC6H4CH2,
R4 = S(CO)SMe
viii
15, R3 =
p
-MeOC6H4CH2,
R4 = H
For structures 5 - 15 : R1, R2 = -O(CH2)4O-
Scheme 2. Reagents and conditions: (i) NaH, (EtO)2P(O)CH2CO2Et,
THF, rt, 84%; (ii) LiAlH4, Et2O, rt, 1 h, 86%; (iii) (OEt)3CCH3,
propionic acid, xylene, 140 °C, 3 h, 66%; (iv) LDA, p-
MeOC6H4CH2Br, THF, 0 °C, 93%; (v) (a) LiAlH4, Et2O, (0 °C!rt),
1 h, 88%, (b) oxalyl chloride, DMSO, Et3N, DCM, ꢁ78 °C, 73%; (vi)
CH2@CHMgBr, THF, 0 °C, 1 h, 80%; (vii) NaH, CS2, MeI, THF,
(0 °C!rt), 6 h, 70%; (viii) n-Bu3SnH, AIBN, C6H6, reflux, 2 h, (78%).
The major fraction (Rf = 0.4) (ethyl acetate–petroleum
ether) isolated in 49% yield comprising a mixture of
alcohols 22 and 23 could also be converted to sequosem-
pervirin A 1 and iso-sequosempervirin A 26 through
alcohols 24 and 25 obtained by inversion of the stereo-
chemistry of the hydroxyl group via Mitsunobu reac-
tion. This transformation unequivocally established the
stereochemistry of alcohols 22–25 obtained from sodium
borohydride reduction of ketones 20 and 21.
attempts to prepare xanthate 13 using the conventional
procedure (NaH–THF, CS2, 0 °C!rt) led to the isola-
tion of dithiocarbonate 14, exclusively, in excellent yield.
The structure of this compound was easily determined
by the appearance of a single olefinic CH2 at d 115.9 in-
stead of the two olefinic CH2’s expected for xanthate 13.
This structure was further confirmed by tributyltin hy-
dride (TBTH) reduction to produce diene 15. The for-
mation of 14 may be explained by a spontaneous [3.3]
rearrangement of the initially formed xanthate 13. [3.3]
Sigmatropic rearrangement of xanthates derived from
allylic alcohols have been reported previously11 and pro-
ceed only at an elevated temperature (ꢀ80 °C). The fac-
In conclusion, we have achieved the first total synthesis
of sequosempervirin A 1. The key steps involve an
orthoester Claisen rearrangement of an appropriately
functionalized cyclohexane derivative and RCM.16 This

S. Maity, S. Ghosh / Tetrahedron Letters 48 (2007) 3355–3358
R1 R2
3357
R1 R2
R1 R2
i, ii
iii, iv
v
+
12
Ar
R3O
16, R1, R2 = -O(CH2)4O-, R3 = H
17, R1, R2 = -O(CH2)4O-, R3 = C(SMe)=S
Ar
Ar
18 R1, R2 = -O(CH2)4O- 19
20 21
R1, R2 = O
OH
OH
OH
OH
OH
OH
vi (for 24 and 25),
vii (for 22 and 23)
+
+
+
+
Ar
Ar
Ar
Ar
22
23
24
25
HO
1
26
HO
For structures 16 - 25 : Ar = p-MeOC6H4
Scheme 3. Reagents and conditions: (i) 11 (4 mol %), DCM, rt, 6 h, 81%; (ii) NaH, CS2, MeI, THF, rt, 3.5 h, 60%; (iii) n-Bu3SnH, AIBN, C6H6,
reflux, 1.5 h, 80%; (iv) 3 N HCl, THF, rt, 1 h, 81%; (v) NaBH4, MeOH, 0 °C, 30 min, 49% (mixture of 22 and 23), 34% (mixture of 24 and 25); (vi)
EtSNa, DMF, 140 °C, 7 h, 50% (for 1), 23% (for 26); (vii) (a) p-NO2C6H4CO2H, PPh3, DEAD, rt, 3 h, (b) 2 N NaOH, THF, rt, overnight, 53%
overall.
10. All new compounds were characterized on the basis of IR,
1H, 13C NMR and HRMS data. Spectral data for selected
compounds: Compound 12: IR (neat) 3454, 1611 cmꢁ1; 1H
NMR (300 MHz, CDCl3): d 1.43–1.48 (2H, m, CH2),
1.52–1.66 (4H, m, CH2), 1.71–1.86 (6H, m, CH2), 1.71–
1.86 (1H, m, CH), 2.61 (1H, dd, J = 4.8, 15.0 Hz, HCH),
2.72 (1H, dd, J = 6.3, 15.0 Hz, HCH), 3.63 (4H, br s,
OCH2), 3.76 (3H, s, OCH3), 4.58 (1H, br s, OCH), 4.94
(1H, d, J = 10.4 Hz, @CH), 5.08–5.09 (2H, m, @CH2),
5.32 (1H, d, J = 11.0 Hz, @CH), 5.57–5.68 (1H, m, CH@),
5.92 (1H, dd, J = 11.0, 17.8 Hz, @CH), 6.76 (2H, d,
J = 8.1 Hz, Ar–CH), 7.07 (2H, d, J = 8.1 Hz, Ar–CH);
13C NMR (75 MHz, CDCl3): d 28.9 (CH2), 29.6 (CH2),
29.70 (CH2), 29.71 (CH2), 29.8 (CH2), 30.8 (CH2), 30.9
(CH2), 43.2 (C), 54.8 (CH), 55.2 (OCH3), 61.4 (OCH2),
61.5 (OCH2), 71.7 (OCH2), 100.8 (C), 113.4 (CH2), 113.5
(CH), 115.8 (CH2), 129.9 (CH), 135.1 (C), 141.3 (CH),
143.6 (CH), 157.4 (C); HRMS m/z 409.2392 [(M+Na)+;
Calcd for C24H34O4Na: 409.2355]: Compound 16: IR
approach has also led to the synthesis of iso-sequosem-
pervirin A 26 and provides scope for asymmetric induc-
tion during the carbonyl reduction step using chiral
reducing agents.
Acknowledgements
S.G. thanks the Department of Science and Technology,
Government of India, for a Ramanna Fellowship. S.M.
thanks CSIR for a research fellowship.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.03.084.
(neat) 3433, 1612 cmꢁ1 1H NMR (300 MHz, CDCl3): d
;
1.24–1.29 (2H, m, CH2), 1.34–1.38 (2H, m, CH2), 1.39–
1.45 (1H, m, CH2), 1.59–1.67 (4H, m, CH2), 1.76–1.87
(3H, m, CH2), 1.76–1.87 (1H, m, CH), 2.52 (1H, t,
J = 13.2 Hz, CH), 2.84 (1H, dd, J = 4.8, 13.4 Hz, CH),
3.63 (2H, br s, OCH2), 3.69 (2H, br s, OCH2), 3.77 (3H, s,
OCH3), 4.61 (1H, d, J = 6.3 Hz, OCH), 5.69 (1H, d,
J = 5.7 Hz, @CH), 6.22 (1 H, d, J = 5.9 Hz, @CH), 6.83
(2H, d, J = 8.4 Hz, Ar–CH), 7.16 (2H, d, J = 8.4 Hz, Ar–
CH); 13C NMR (75 MHz, CDCl3): d 29.6 (CH2), 29.8
(CH2), 30.3 (CH2), 30.8 (CH2), 31.1 (CH2), 33.7 (CH2),
34.1 (CH2), 49.9 (C), 55.2 (OCH3), 60.3 (CH), 61.6
(OCH2), 61.7 (OCH2), 82.0 (OCH), 100.6 (C), 114.2
(CH), 129.7 (CH), 132.3 (CH), 133.1(C), 138.9 (CH), 157.9
(C); HRMS m/z 381.2038 [(M+Na)+; Calcd for
C22H30O4Na: 381.2042]: Compound 1: mp = 169–170 °C;
1H NMR (300 MHz, CD3OD): d 1.18–1.19 (1H, m, CH),
1.29–1.31 (1H, m, CH), 1.55–1.64 (1H, m, CH2), 1.69–1.71
(2H, m, CH2), 1.81–1.86 (3H, m, CH2), 1.99–2.05 (1H, m,
CH), 1.99–2.05 (1H, m, CH2), 2.15–2.16 (1H, m, CH2),
2.25 (1H, t, J = 12.68 Hz, CH2), 2.79 (1H, dd, J = 2.84,
13.3 Hz, CH2), 3.84–3.86 (1H, m, OCH), 5.62–5.64 (1H,
m, @CH), 5.86 (1H, d, J = 5.67 Hz, @CH), 6.68 (2H, d,
J = 8.37 Hz, Ar–CH), 6.97 (2H, d, J = 8.34 Hz, Ar–CH);
13C NMR (75 MHz, CD3OD): d 28.1 (CH2), 31.5 (CH2),
32.2 (CH2), 33.0 (CH2), 36.1 (CH2), 37.5 (CH2), 50.6
(CH), 50.9 (C), 68.3 (CH), 116.0 (CH), 129.3 (CH), 130.7
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