Synthetic studies on schisandra nortriterpenoids. Stereocontrolled synthesis of enantiopure C-5- epi ABC ring systems of micrandilactone A and lancifodilactone G using RCM

Article abstract of DOI:10.1021/jo1006448

A stereocontrolled approach for the construction of ABC ring systems of micrandilactone A and lancifodilactone G has been developed. The synthesis involves construction of an enantiopure functionalized cycloheptene derivative 17 through RCM of the dienol 14 prepared from the known d-mannitol-derived unsaturated ester 12. A remarkable regioselectivity during hydroboration of the cycloheptene derivative 17 was observed during its transformation to the cycloheptanone 20. RCM of the diene 24 prepared stereoselectively from 20 gave the spiro-dihydrofuran 25. The ketal unit in 25 was then converted into the carbinols 28 and 36. A bromonium ion initiated highly stereocontrolled intramolecular etherification in 28 and 37 led to the tricyclic ethers 29 and 38, respectively. Reductive removal of bromine from 29 and 38 followed by RuO₄ oxidation led to the furo-furanone derivatives 31 and 40, the C-5-epi ABC ring systems of the schisandra nortriterpenoids 1 and 2.

Full text of DOI:10.1021/jo1006448

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Synthetic Studies on Schisandra nortriterpenoids. Stereocontrolled
Synthesis of Enantiopure C-5-epi ABC Ring Systems of Micrandilactone
A and Lancifodilactone G Using RCM
Soumitra Maity, Kiran Matcha, and Subrata Ghosh*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Kolkata 700032, India
ocsg@iacs.res.in
Received April 5, 2010
A stereocontrolled approach for the construction of ABC ring systems of micrandilactone A and
lancifodilactone G has been developed. The synthesis involves construction of an enantiopure
functionalized cycloheptene derivative 17 through RCM of the dienol 14 prepared from the known D-
mannitol-derived unsaturated ester 12. A remarkable regioselectivity during hydroboration of the
cycloheptene derivative 17 was observed during its transformation to the cycloheptanone 20. RCM
of the diene 24 prepared stereoselectively from 20 gave the spiro-dihydrofuran 25. The ketal unit in 25
was then converted into the carbinols 28 and 36. A bromonium ion initiated highly stereocontrolled
intramolecular etherification in 28 and 37 led to the tricyclic ethers 29 and 38, respectively. Reductive
removal of bromine from 29 and 38 followed by RuO4 oxidation led to the furo-furanone derivatives
31 and 40, the C-5-epi ABC ring systems of the schisandra nortriterpenoids 1 and 2.
Introduction
and schintrilactone B 7 (wuweiziartane type),2 etc. (Figure 1).
Micrandilactones A 1 and B 3 were isolated2 from the stems and
leaves of S. micrantha, lancifodilactone G 2 was isolated3 from
stems and leaves of S. lancifolia, rubriflordilactone B 44 was
isolated from S. rubriflora, and compounds 5-75 were isolated
from S. chinensis. Many of the compounds isolated from these
plants possess a wide range of medicinal properties. For
example, compounds 1 and 3-7 exhibit anti-HIV activity,
Schisandra nortriterpenoids1 are a group of recently disco-
vered highly oxygenated structurally diverse polycyclic com-
pounds isolated from various species of Schisandracea family.
Plants of this family are widely distributed throughout South-
east Asia and North America. Many of the species of this family
have been used as folk medicines in China over the years.
Biosynthetically they are derived from cycloartane.1 On the
basis of the structural pattern encountered in compounds of this
family, they can be classified into the following categories:
schisanartane, schiartane, 18-norschiartane, 18(13f14)-abeo-
schiartane, preschisanartane, and wuweiziartane. Representa-
tive examples include micrandilactone A 1 and lancifodilactone
G 2 (schisanartane type), micrandilactone B 3 (schiartane type),
rubriflordilactone B 4 (18-norschiartane type), wuweizidilac-
tone C 5 (18(13f14)-abeo-schiartane type), schintrilactone A 6
(2) (a) Li, R.; Zhao, Q.; Li, S.; Han, Q.; Sun, H.; Lu, Y.; Zhang, L.; Zheng,
Q. Org. Lett. 2003, 5, 1023–1026. (b) Li, R. T.; Han, Q. B.; Zheng, Y. T.;
Wang, R. R.; Yang, L. M.; Lu, Y.; Sang, S. Q.; Zheng, Q. T.; Zhao, Q. S.;
Sun, H. D. Chem. Commun. 2005, 2936–2938.
(3) Xiao, W. L.; Zhu, H. J.; Shen, Y. H.; Li, R. T.; Li, S. H.; Sun, H. D.; Zheng,
Y. T.; Wang, R. R.; Lu, Y.; Wang, C.; Zheng, Q. T. Org. Lett. 2006, 8, 801.
(4) Xiao, W. L.; Yang, L. M.; Gong, N. B.; Wu, L.; Wang, R. R.; Pu, J. X.;
Li, X. L.; Huang, S. X.; Zheng, Y. T.; Li, R. T.; Lu, Y.; Zheng, Q. T.; Sun,
H. D. Org. Lett. 2006, 8, 991–994.
(5) For isolation of wuweizidilactone C, see: (a) Huang, S. X.; Yang,
L. B.; Xiao, W. L.; Lei, C.; Liu, J. P.; Lu, Y.; Weng, Z. Y.; Li, L. M.; Li, R. T.;
Yu, J. L.; Zheng, Q. T.; Sun, H. D. Chem.—Eur. J. 2007, 13, 4816–4822. For
isolation of schintrilactones A and B, see: (b) Huang, S. X.; Yang, J.; Huang,
H.; Li, L. M.; Xiao, W. L.; Li, R. T.; Sun, H. D. Org. Lett. 2007, 9, 4175–4178.
(1) Xiao, W. L.; Li, R. T.; Huang, S. X.; Pu, J. X.; Sun, H. D. Nat. Prod.
Rep. 2008, 25, 871–891.
4192 J. Org. Chem. 2010, 75, 4192–4200
Published on Web 05/21/2010
DOI: 10.1021/jo1006448
r
2010 American Chemical Society

Maity et al.
JOCArticle
FIGURE 1. Naturally occurring nortriterpenoids.
SCHEME 1. Retrosynthetic Plan
natural products upon annulation of the residual rings onto the
seven-membered ring. Thus, we initially focused on developing
a methodology that would enable construction of the fragment
8a as well as 8b from a common precursor. A number of
approaches6 dealing with the synthesis of various parts of some
of these compounds have been reported.
However, as far as the construction of the furofuranone ring
system is concerned, there are only a few reports. In these
approaches, an oxy-Michael addition to either a butenolide6h,i
or to an enoate6b,e with concomitant lactonization was em-
ployed as the key step. Using this concept, synthesis of the ABC
ring unit present in micrandilactone A and lancifodilactone G
has been achieved recently.6b,e To the best of our knowledge
there is no report of any approach that addresses the synthesis of
the ABC ring of both series represented by compounds 1 and 2.
We planned to develop a general protocol from a common
precursor for access to the ABC rings of both series of natural
products represented by structures 8a and 8b (Scheme 1). The
key concept in our approach relies on bromonium ion initiated
intramolecular etherification in the spiro-dihydrofuran deriva-
tive 9 followed by oxidation of the bis-tetrahydrofuran deriva-
tive to lead to 8. The oxa-spiro[4.6]undecene derivatives 9a and
9b would be available from RCM7 of the diene 10, the ketal unit
being used as the surrogate to both gem-dimethyl and methyl-
hydroxymethyl units. Compound 10 would be available from
the highly functionalized cycloheptene derivative 11. Herein we
report preliminary results of our investigation based on this plan
culminating in the synthesis of the C-5-epi ABC core present in
both series represented by 1 and 3-7 as well as 2.
and the extract of the plant from which 2 was isolated is
traditionally used for the treatment of rheumatic lumbago
and traumatic injury and related diseases. Compound 2 also
exerts cytotoxicity against C8166 cells.
The densely functionalized novel polycyclic architecture
with multiple stereogenic centers presents a considerable
synthetic challenge. Interest in the synthesis of these com-
pounds has further been increased by the broad range biolo-
gical activity associated with them. We have recently ini-
tiated a program toward the development of a route for entry
into nortriterpenoids of the Schisandracea family.
A common structural feature of the compounds in this family
is the presence of the fragments 8a and 8b, which represent the
ABC core. While the structural prototype 8a is present in a
majority of the schisandra nortriterpenoids including 1 and
3-7, fragment 8b is present in 2 (Scheme 1). We thought that
construction of these fragments 8a and 8b having a functiona-
lized seven-membered ring would enable their elaboration to the
Results and Discussion
The synthesis commenced with the construction of the
functionalized cycloheptanone derivative 20 in enantiomeri-
cally pure form as delineated in Scheme 2. We initially
focused our attention to demonstrate the feasibility of this
(7) For excellent accounts on RCM, see: (a) Grubbs, R. H.; Miller, S. J.;
€
1997, 4, 285–299. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997,
36, 2036–2056. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450. (e) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
(6) (a) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.; Deng, L.; Chen, J.; Yang, Z.
Org. Lett. 2005, 7, 885–888. (b) Zhang, Y. D.; Tang, Y. F.; Luo, T. P.; Shen,
J.; Chen, J. H.; Yang, Z. Org. Lett. 2006, 8, 107–110. (c) Zhang, Y. D.; Ren,
W. W.; Lan, Y.; Xiao, Q.; Wang, K.; Xu, J.; Chen, J. H.; Yang, Z. Org. Lett.
2008, 10, 665–668. (d) Lai, K. W.; Paquette, L. A. Org. Lett. 2008, 10, 2115–
2118. (e) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 2111–2113.
(f) Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10, 3781–3784. (g) Cordonnier,
M-C. A.; Kan, S. B. J.; Anderson, E. A. Chem. Commun. 2008, 5818–5820.
(h) Mehta, G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474–2477. (i) Mehta,
G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2009, 50, 6597–6600.
Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452. (b) Furstner, A. Top. Catal.
€
(f) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012–3043. (g) Deiters, A.;
Martin, S. F. Chem. Rev. 2004, 104, 2199–2238. (h) Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527. (i) Ghosh, S.;
Ghosh, S.; Sarkar, N. J. Chem. Sci. 2006, 118, 223–235. (j) Chattopadhyay,
S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B.
Tetrahedron 2007, 63, 3919–3952.
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SCHEME 2. Synthesis of Functionalized Cycloheptane Deri-
column chromatography to give 15 and 16 in 38% and 58%
yields, respectively. The minor diastereoisomer 15 was iso-
merized to 16 through Mitsunobu protocol. The stereochem-
ical assignment to the hydroxyl group in 16 could not be
made at this stage. The hydroxyl group in 16 was then
protected to provide the benzyl ether 17 in 85% yield. The
vative 20a
cycloheptene derivative 17 was next treated with BH3 Me2S,
3
and the resulting alkyl borane was oxidized in situ with
alkaline H2O2 to give a mixture of cycloheptanols (ca. 4:1).
Careful chromatography of this mixture led to isolation of
the compounds 18 (Rf 0.7) and 19 (Rf 0.5), each of them being
obtained as diastereomeric mixtures in 64% and 16% yields,
respectively. The cycloheptanols 18 and 19 were oxidized
separately by DMP to afford the cycloheptanones 20 and 21
in quantitative yield. The structures of the cycloheptanones
were established by comparing the 13C chemical shifts of the
C3-methine carbons of 20 with that of 21. The C3-methine
carbon next to the carbonyl group is expected to be de-
shielded over the one that is one carbon away from the
carbonyl group. The cycloheptanone derivative obtained
from oxidation of the major cycloheptanols with higher Rf
value appeared at δ 51.9, while the same carbon in the
cycloheptanone derivative arising from cycloheptanols with
lower Rf value appeared at δ 35.8. Thus the former cyclo-
heptanone derivative was assigned the structure 20, and the
latter was assigned the regioisomeric structure 21. This
indicated that hydroboration of the cycloheptene derivative
17 proceeded to produce predominantly the regioisomer 18.
Regioselective hydroboration10 of the unsymmetrical cyclo-
heptene 17 is interesting. Such regioselectivity during hydro-
boration has been observed only in alkenes where there is an
oxygen functionality at the allylic position. Regioselectivity
observed in the present case probably arises through addi-
tion of borane through the complex 22 in which borane is co-
ordinated to the homoallylic oxygen atom of the ketal unit.
With the functionalized cycloheptanone 20 in hand, next
we focused our attention on the construction of the furofura-
none unit on it. Toward this end, the cycloheptanone 20 was
reacted with vinylmagnesium bromide to afford the adduct
23 in 65% yield as a single diastereomer (Scheme 3). We
expected that addition would take place through a metal-
coordinated chelate to produce the desired adduct from the
side of the substituent bearing the ketal unit. This would then
lead to 4-epi-28 (Scheme 3), which on bromoetherification
would give rise to a tricycle with C-1, C-4, and C-5 relative
stereochemistry the same as that present in the ABC ring of
Schisandra natural products. Disappointingly, vinylmagne-
sium bromide added to the cycloheptanone 20 exclusively
from the face opposite to the bulky ketal unit. This could be
ascertained only after transformation of 23 to the bromo bis-
tetrahydrofuran derivative 29. The compound 23 was then
converted into the allyl ether 24. Exposure of 24 to Grubbs I
precatalyst resulted in smooth formation of the dihydrofur-
an derivative 25 in 94% yield. Acid-induced deketalization of
25 afforded the diol 26 in excellent yield. The diol 26 was then
transformed into the methyl ketone 27 through a sequence of
high yielding steps involving periodate cleavage of the diol
and addition of MeMgI to the resulting aldehyde followed
by DMP oxidation. Addition of MeMgI to 27 afforded 28.
a For structures 12-22: R1, R2 = -(CH2)5-.
synthetic plan. For this purpose the unsaturated ester 12 was
chosen as this is readily available8a from D-mannitol com-
pared to its diastereoisomer epimeric at C-3.8b According to
the retrosynthetic plan, the ester 12 was expected to provide
the enantiomer of 8a. Eventually, the ester 12 turned out to
be the right choice. It led to C-5-epi-8a (vide infra) having the
desired stereochemistry at all of the stereogenic centers
except the one at C-5, which can be inverted in one of the
subsequent steps during total synthesis. The ester 12 was
transformed into the aldehyde 139 using a reduction-oxida-
tion sequence. The aldehyde 13 on reaction with 4-butenyl
magnesium bromide afforded in 90% yield an inseparable
mixture of alcohols 14 (ca. 3:2) as revealed by 13C NMR
spectra. RCM of the mixture of dienols 14 with Grubbs I did
not proceed at all. However, with Grubbs II ring closure
proceeded smoothly to afford a mixture of the cyclohepte-
nols 15 and 16. The cycloheptenols could be separated by
(8) (a) Matcha, K.; Ghosh, S. Tetrahedron Lett. 2008, 49, 3433–3436.
(b) Banerjee, S.; Ghosh, S.; Sinha, S.; Ghosh, S. J. Org. Chem. 2005, 70,
4199–4202.
(9) Ghosh, S.; Bhaumik, T.; Sarkar, N.; Nayek, A. J. Org. Chem. 2006, 71,
9687–9694.
(10) (a) Brown, H. C.; Knights, E. F. J. Am. Chem. Soc. 1968, 90, 4439–
4444. (b) Pasto, D. J.; Hickman, J. J. Am. Chem. Soc. 1968, 90, 4445–4449.
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SCHEME 3. Synthesis of C-5-epi ABC Core of Compounds 1 and 3-7a
a For structures 23-25: R1, R2 = -(CH2)5-.
With the availability of the precursor 28, we proceeded for its
bromonium ion initiated cyclization.11 Compound 28 was
treated with NBS in DMSO. As expected, cyclization pro-
ceeded stereoselectively through the bromonium ion inter-
mediate 28i formed by addition of bromine from the least
hindered re face of the alkene. The bromo ether 29 was
obtained exclusively in quantitative yield. The stereo-
chemical assignment to 29 was established through single
crystal X-ray12 structure determination. Reductive removal
of bromine from 29 could be achieved with TBTH in near
quantitative yield to afford the bis-tetrahydrofuran deriva-
tive 30. Finally, oxidation of 30 with RuCl3(cat.)/NaIO4
proceeded smoothly to afford the furofuranone derivative
31 in 76% isolable yield. It may be noted that oxidation of
benzylic group to benzoate ester also took place during
oxidation of the tetrahydrofuran ring in 30.
butenolide 32 to afford stereoselectively the tricyclic lactone 33 in
72% yield. The structure of this compound was initially deter-
mined by its transformation to the benzoate 31 on treatment with
RuCl3(cat.)/NaIO4. This structural assignment was confirmed
through single crystal X-ray analysis.12 Finally, the projected
intermediate could be prepared as follows. Debenzylation of 30
was achieved through hydrogenolysis to afford the hydroxy-com-
pound 34 in excellent yield. Oxidation of the tetrahydrofuran unit
in 34 with RuCl3/NaIO4 proceeded smoothly with simultaneous
oxidation of the hydroxyl group to afford the cycloheptanone 35
in excellent yield. This approach thus led to the synthesis of C-5-
epi ABC core of schisandra terpenes. The C-7 carbonyl group can
be employed not only to annulate rings of appropriate size onto
seven-membered ring but also to invert the configuration at the
C-5 stereogenic center through reduction of the conjugated enone
system derivable in principle at a late stage in the total synthesis.
With the success of the above protocol in synthesizing the
diastereoisomeric ABC ring system of 1 and 3-7, we next em-
barked upon its extension for the construction of the diastereo-
isomeric ABC ring system present in lancifodilactone G 2
(Scheme 4). The synthesis began with selective protection of the
primary hydroxyl group of 26 as silyl ether followed by oxidation
of the secondary alcohol to afford the ketone 36. Addition of
methylmagnesium iodide to 36 afforded an inseparable mixture
of carbinols 37 in a 3:2 ratio in 90% yield. This mixture on
treatment with NBS in DMSO gave quantitatively a mixture of
two tricyclic bromides 38 and 39. The major diastereoisomer in
this mixture was separated by column chromatography to afford
At this stage we thought of exploring an alternative protocol.
Thus, the dihydrofuran 28 was treated with Jones reagent with
the objective of synthesizing the butenolide 32. Amazingly,oxida-
tion of the dihydrofuran unit took place with spontaneous
intramolecular 1,4-addition of the tertiary alcohol to the resulting
(11) Zhong, H. M.; Sohn, J. H.; Rawal, V. H. J. Org. Chem. 2007, 72, 386–
397.
(12) Crystallographic data for compounds 29 and 33 have been deposited
with the Cambridge Crystallographic Data Center as supplementary pub-
lication nos. CCDC 762931and 759611, respectively. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. Fax: þ44 1223-336033. E-mail: deposit@ccdc.
cam.ac.uk.
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SCHEME 4. Synthesis of C-5-epi ABC Core of Lancifodilactone G 2
the bromo-ether 38 in 54% yield. The assignment of stereoche-
mistry to 38 was based on analogy to the formation of the bro-
moether 29 from reaction of 28 with NBS. Reductive removal of
bromine with TBTH followed by oxidation with RuCl3/NaIO4
finally afforded the tricyclic lactone 40 in 74% yield. The assign-
ment of stereochemistry (Figure 2) to the lactone 40 is based on
analysis of its NMR spectral data (HSQC, COSY, NOESY and
NOE). Significant NOE enhancements observed among the
marked protons corroborated the above structural assignment.
followed by bromonium ion initiated cyclization to form the
bis-tetrahydrofuran derivative. Oxidation of the latter then
furnished the furo-furanone system.
Experimental Section
(S)-3-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)nona-1,8-dien-5-ol (14).
4-Bromo-1-butene (0.95 mL, 9.37 mmol) was added dropwise to a
stirred suspension of magnesium turnings (450 mg, 18.74 mmol) in
THF (15 mL) at 0 °C, and the mixture was stirred for 1 h to produce
a clear solution. A solution of the aldehyde 13 (1.4 g, 6.24 mmol) in
THF (10 mL) was added dropwise to this solution at 0 °C and
allowed to stir for 1 h. The reaction mixture was quenched with
saturated aqueous NH4Cl solution (1 mL). Usual workup of the
reaction mixture followed by column chromatography (15% Et2O/
petroleum ether) afforded an inseparable mixture of dienols 14 (1.57
g, 90%) as liquid: [R]25D þ2.3 (c 5.2, CHCl3);νmax (film) 3445, 2935,
1640, 1448 cm-1; 1H NMR (300 MHz, CDCl3) δ (for the mixture)
5.88-5.74 (m, 1H), 5.65-5.46 (m, 1H), 5.13-5.02 (m, 2H),
4.99-4.92 (m, 2H), 3.96-3.76 (m, 2H), 3.69-3.55 (m, 2H), 2.73
(br s, 1H), 2.38-2.30 (m, 1H), 2.24-2.07 (m, 2H), 1.81-1.70 (m,
1H), 1.60-1.43 (m, 11H), 1.37 (br s, 2H); 13C NMR (75 MHz,
CDCl3) δ (for major isomer) 138.8, 138.2, 117.2, 114.7, 110.1, 78.4,
69.4, 68.3, 46.6, 40.6, 37.4, 36.4, 35.3, 30.2, 25.2, 24.1, 24.0; (for
minor isomer) 138.7, 138.4, 117.0, 114.7, 110.1, 78.0, 69.5, 68.3, 45.8,
40.7, 36.5, 36.1, 35.2, 30.1, 25.2, 24.1, 24.0; HRMS (ESI) m/z [M þ
Na]þ, calcd for C17H28O3Na 303.1936; found 303.1936.
FIGURE 2. COSY, NOESY, and NOE analysis of 40.
The minor diastereoisomer 39 was converted into the
tricycle 41, in 72% yield. The structure of the tricyclic lactone
41 was established through analysis of its NMR spectra
(HSQC, COSY and NOESY) as depicted in Figure 3.
(1R,3S)-3-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)cyclohept-4-enol
(15) and (1S,3S)-3-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)cyclo-
hept-4-enol (16). A solution of diastereoisomeric dienols 14
(100 mg, 0.35 mmol) in dichloromethane (20 mL) was treated
with Grubbs second generation catalyst (8 mg, 0.01 mmol)
under Ar atmosphere and stirred at rt for 6 h. The residual mass
obtained after removal of solvent was chromatographed (15%
EtOAc/petroleum ether) to afford 15 (33 mg, 38%) and 16 (50
mg, 58%) as a colorless liquid. Compound 15: [R]27D þ33.4 (c
4.0, CHCl3); νmax (film) 3435, 3013, 2933, 1448 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.85-5.77 (m, 1H), 5.50 (dd, J = 11.0, 4.0
Hz, 1H), 4.21-4.15 (m, 1H), 4.03-3.96 (m, 2H), 3.63-3.56 (m,
1H), 2.80 (br s, 1H), 2.36-2.27 (m, 1H), 1.95-1.80 (m, 3H),
FIGURE 3. COSY and NOESY analysis of 41.
1.75-1.65 (m, 3H), 1.63-1.51 (m, 8H), 1.40-1.35 (m, 2H); 13
C
Conclusion
NMR (75 MHz, CDCl3) δ 133.0, 132.0, 109.6, 78.2, 69.5, 67.4,
37.3, 36.5, 36.2, 35.1, 34.0, 25.3, 24.1, 24.0, 22.7; HRMS (ESI)
m/z [M þ Na]þ, calcd for C15H24O3Na 275.1628, found 275.1625.
In conclusion, we have developed a protocol that allows enan-
tiopure construction of the C-5-epi ABC ring system present in 1
and 3-7. The same protocol has been extended for the con-
struction of the C-5-epi ABC core present in lancifodilactone
G 2. The key steps involve RCM to form spirodihydrofuran
Compound 16: [R]25 þ16.5 (c 4.9, CHCl3); νmax (film) 3389,
D
1
3377, 2933, 1651, 1448 cm-1; H NMR (300 MHz, CDCl3) δ
5.87-5.79 (m, 1H), 5.47 (d, J = 10.9 Hz, 1H), 4.03-3.98 (m,
2H), 3.79-3.72 (m, 1H), 3.62-3.55 (m, 1H), 2.31 (br s, 1H),
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Maity et al.
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2.23-1.91 (m, 5H), 1.59 (br s, 4H), 1.55 (br s, 4H), 1.37-1.27 (m,
2H), 1.25-1.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 132.5,
131.6, 109.5, 78.2, 74.1, 67.1, 38.4, 38.2, 36.3, 35.3, 34.7,
25.1, 24.0, 23.7, 23.0; HRMS (ESI) m/z [M þ Na]þ, calcd for
C15H24O3Na 275.1628, found 275.1623.
20 mL) was performed. The organic layer was dried and concen-
trated in vacuo. Purification of the residual mass by column
chromatography (20% EtOAc/petroleum ether) afforded mixture
of cycloheptanols 18 (202 mg, 64%) and 19 (50 mg, 16%) as a
colorless oil. Compound 18: [R]25 þ11.5 (c 2.3, CHCl3); νmax
D
1
(film) 3454, 2933, 2860, 1496, 1450 cm-1; H NMR (300 MHz,
(1S,3S)-3-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)cyclohept-4-enol
(16). To a solution of cycloheptenol 15 (900 mg, 3.57 mmol) in
THF were added triphenyl phosphine (1.87 g, 7.14 mmol),
diisopropyl azodicarboxylate (1.4 mL, 7.14 mmol), and p-nitro-
benzoic acid (1.2 g, 7.14 mmol), and the reaction mixture was
stirred for 2 h. After being diluted with Et2O (30 mL), the
reaction mixture was washed with saturated aqueous NaHCO3
solution and brine, dried over Na2SO4, and concentrated under
reduced pressure. The resulting crude residue was purified by
column chromatography (5% Et2O/petroleum ether) to give
p-nitrobenzoate derivative (1.35 g, 94%) as a colorless liquid:
[R]24D -20.4 (c 4.9, CHCl3); νmax (film) 2936, 1720, 1608, 1529,
1448 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J = 8.7 Hz,
2H), 8.18 (d, J = 8.6 Hz, 2H), 5.92-5.89 (m, 1H), 5.55 (d, J =
10.8 Hz, 1H), 5.24-5.17 (m, 1H), 4.10-4.02 (m, 2H), 3.68-3.62
(m, 1H), 2.46 (br s, 1H), 2.36-2.26 (m, 2H), 2.19-2.1 (m, 2H),
1.62 (br s, 5H), 1.55 (br s, 5H), 1.47-1.37 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 163.8, 150.5, 136.3, 132.5, 131.8, 130.8 (ꢀ2),
123.5 (ꢀ2), 109.9, 78.2, 77.9, 67.3, 38.5, 36.5, 35.0 (ꢀ2), 32.2,
25.2, 24.1, 23.9, 23.1; HRMS (ESI) m/z [M þ Na]þ, calcd for
C22H27NO6Na 424.1737, found 424.1736.
CDCl3) δ (for the mixture) 7.28-7.20 (m, 5H), 4.53-4.42 (m, 2H),
4.28-4.10 (m, 1H), 4.06-3.89 (m, 2H), 3.87-3.79 (m, 1H),
3.74-3.57 (m, 1H), 3.42-3.32 (m, 1H), 2.14-1.84 (m, 2H),
1.82-1.67 (m, 2H), 1.64-1.48 (m, 10H), 1.38-1.30 (m, 3H),
1.26-1.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ (for major
isomer) 138.6, 128.3 (ꢀ2), 127.5 (ꢀ2), 127.4, 109.4, 80.4, 78.4, 70.8,
70.4, 65.7, 43.1, 35.8, 35.4, 34.7, 34.3, 31.4, 25.0, 24.0, 23.7, 17.1; (for
minor isomer) 138.3, 128.2 (ꢀ2), 127.3, 127.2 (ꢀ2), 109.4, 78.8,
76.9, 70.8, 70.1, 67.3, 43.5, 36.6, 36.2, 34.6, 32.2, 28.9, 25.1, 23.9,
23.8, 16.7; HRMS (ESI) m/z [M þ Na]þ, calcd for C22H32O4Na
383.2198, found 383.2194. Compound 19: [R]27 þ6.4 (c 4.1,
D
CHCl3); νmax (film) 3439, 3417, 2933, 2860, 1496, 1450 cm-1; 1H
NMR (300 MHz, CDCl3) δ (for the mixture) 7.27-7.18 (m, 5H),
4.47(brs, 2H), 4.09-3.90 (m, 2H), 3.86-3.67 (m, 2H), 3.57-3.52
(m, 1H), 3.50-3.36 (m, 1H), 2.36-2.01 (m, 2H), 1.97-1.62 (m,
2H), 1.58-1.40 (m, 10H), 1.33 (br s, 3H), 1.28-1.10 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ (for major isomer) 138.8, 128.3 (ꢀ2),
127.6 (ꢀ2), 127.4, 109.4, 79.3, 79.2, 70.3, 69.1, 67.1, 38.9, 36.8,
36.3, 34.9, 33.2, 30.8, 28.7, 25.2, 24.0, 23.8; (for minor isomer)
138.8, 128.3 (ꢀ2), 127.5 (ꢀ2), 127.4, 108.8, 79.1, 77.6, 71.7, 70.1,
66.9, 39.9, 36.9, 36.3, 35.3, 34.7, 31.6, 27.4, 25.2, 24.0, 23.8;
HRMS (ESI) m/z [M þ Na]þ, calcd for C22H32O4Na 383.2198,
found 383.2197.
The p-nitrobenzoate derivative (1.05 g, 2.61 mmol) was
treated with aqueous NaOH solution (5.3 mL, 10.46 mmol, 2
N in H2O) in THF (20 mL) at rt for overnight. After being
diluted with Et2O (50 mL), the reaction mixture was washed
with brine solution, dried over Na2SO4, and concentrated under
reduced pressure. The crude residue was purified by column
chromatography (15% EtOAc/petroleum ether) to provide
cycloheptenol 16 (627 mg, 95%) as a colorless oil.
(2R,4S)-4-(Benzyloxy)-2-((S)-1,4-dioxaspiro[4.5]decan-2-yl)-
cycloheptanone (20). To a solution of the cycloheptanol deriva-
tive 18 (60 mg, 0.16 mmol) in CH2Cl2 (5 mL) at rt was added
DMP (85 mg, 0.20 mmol) portionwise, and the reaction mixture
was allowed to stir for 2 h.The reaction mixture was quenched
with 10% Na2S2O3 solution (2 mL) doped with NaHCO3 at ice-
cold condition and stirred vigorously until the organic layer
became transparent. The organic layer was washed with brine,
dried over Na2SO4, and concentrated in vacuo. Purification of
the residual mass by column chromatography (12% Et2O/
petroleum ether) afforded cycloheptanone 20 (59 mg, 99%) as
(S)-2-((1S,6S)-6-(Benzyloxy)cyclohept-2-enyl)-1,4-dioxaspiro-
[4.5]decane (17). To a magnetically stirred suspension of NaH
(508 mg, 12.7 mmol, 60% in oil), freed from adhering oil by
repeated washing with petroleum ether, in dry THF (20 mL) at
0 °C was added dropwise a solution of the alcohol 16 (800 mg, 3.17
mmol) in dry THF (15 mL) under N2 atmosphere. The mixture
was allowed to reflux for 1 h, and then to it was added HMPA (0.8
mL) dropwise followed by benzyl bromide (0.94 mL, 7.93 mmol).
After refluxing for an additional 6 h, the reaction mixture was
cooled to 0 °C and quenched by adding saturated aqueous NH4Cl
solution (1 mL). Usual workup of the reaction mixture followed
by column chromatography (7% Et2O/petroleum ether) afforded
the benzyl ether 17 (923 mg, 85%) as a colorless oil: [R]25D þ17.4 (c
3.7, CHCl3); νmax (film) 3013, 2935, 1653, 1496 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 5.91-5.85 (m, 1H), 5.55
(dd, J = 11.4, 2.5 Hz, 1H), 4.60 (s, 2H), 4.10-4.02 (m, 2H), 3.67-
3.63 (m, 1H), 3.53-3.49 (m, 1H), 2.37-2.26 (m, 3H), 2.12-1.92
a colorless oil: [R]26 -35.2 (c 5.0, CHCl3); νmax (film) 2934,
D
1
2860, 1699, 1450 cm-1; H NMR (300 MHz, CDCl3) δ 7.36-
7.25 (m, 5H), 4.58 (dd, J = 17.7, 12.0 Hz, 2H), 4.30-4.22 (m,
1H), 4.15 (dd, J = 8.5, 6.1 Hz, 1H), 3.51-3.44 (m, 2H), 2.61-
2.52 (m, 1H), 2.50-2.44 (m, 2H), 2.29-2.21 (m, 1H), 1.91-1.84
(m, 1H), 1.67-1.57 (m, 10H), 1.53-1.40 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 213.9, 138.6, 128.5 (ꢀ2), 127.7 (ꢀ2), 127.6,
109.2, 79.5, 75.5, 70.5, 68.8, 51.9, 43.5, 36.8, 35.3, 34.8, 32.8,
25.3, 24.2, 23.9, 19.7; HRMS (ESI) m/z [M þ Na]þ, calcd for
C22H30O4Na 381.2042, found 381.2047.
(3S,5S)-5-(Benzyloxy)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)-
cycloheptanone (21). Following the procedure of oxidation, the
above carbinol 19 (40 mg, 0.11 mmol) was oxidized with DMP (56
mg, 0.14 mmol) to afford the title compound 21 (39 mg, 98%) as a
colorless liquid: [R]27 þ36.6 (c 3.6, CHCl3); νmax (film) 2935,
2860, 1699, 1450 cm-1D; 1H NMR (300 MHz, CDCl3) δ 7.30-7.19
(m, 5H), 4.50 (s, 2H), 3.96-3.88 (m, 2H), 3.55-3.51 (m, 1H),
3.43-3.34 (m, 1H), 2.45-2.31 (m, 4H), 2.15-2.08 (m, 1H), 1.87-
1.61 (m, 2H), 1.53 (br s, 4H), 1.49 (br s, 4H), 1.38-1.29 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 212.2, 138.5, 128.5 (ꢀ2), 127.7,
127.6 (ꢀ2), 109.9, 79.2, 78.5, 70.6, 66.7, 45.4, 38.9, 38.0, 36.4, 35.8,
34.9, 30.0, 25.2, 24.0, 23.9; HRMS (ESI) m/z [M þ Na]þ, calcd for
C22H30O4Na 381.2042, found 381.2043.
(m, 2H), 1.65 (br s, 5H), 1.61 (br s, 4H), 1.57-1.41 (m, 3H); 13
C
NMR (75 MHz, CDCl3) δ 139.1, 132.7, 131.6, 128.5 (ꢀ2), 127.6,
127.6, 127.5, 109.6, 81.0, 78.6, 70.2, 67.1, 38.3, 36.6, 35.5, 35.0,
32.3, 25.3, 24.1, 23.9, 23.4; HRMS (ESI) m/z [M þ Na]þ, calcd for
C22H30O3Na 365.2090, found 365.2093.
(2S,4S)-4-(Benzyloxy)-2-((S)-1,4-dioxaspiro[4.5]decan-2-yl)cy-
cloheptanol (18) and (3R,5S)-5-(Benzyloxy)-3-((S)-1,4-dioxas-
piro[4.5]decan-2-yl)cycloheptanol (19). To a solution of the
cycloheptene derivative 17 (300 mg, 0.88 mmol) in dry THF
(10 mL) was added borane dimethylsulfide complex solution
(1.31 mL, 2.63 mmol, 2.0 M in THF) at -20 °C under argon. The
mixture was then warmed to 0 °C and stirred at that temperature
for an additional 2 h. The reaction mixture was then oxidized
by sequential addition of MeOH (0.54 mL, 10.5 mmol), NaOH
(2.64 mL, 7.92 mmol, 3 N in water), and H2O2 (2.8 mL, 18.6
mmol, 30%). The mixture was then stirred overnight at rt, water
(5 mL) was added, and then an extraction with EtOAc (3 ꢀ
(1S,2R,4S)-4-(Benzyloxy)-2-((S)-1,4-dioxaspiro[4.5]decan-2-
yl)-1-vinylcycloheptanol (23). To a solution of the cyclohepta-
none derivative 20 (350 mg, 0.97 mmol) in THF (10 mL) was
added vinylmagnesium bromide (3.0 mL, 3.0 mmol, 1 M in
THF), and the resulting mixture was refluxed for 3 h. Then the
J. Org. Chem. Vol. 75, No. 12, 2010 4197

Maity et al.
JOCArticle
resulting mixture was cooled to 0 °C, quenched with saturated
aqueous NH4Cl solution, extracted with EtOAc (3 ꢀ 10 mL),
washed with brine, and dried over Na2SO4. The crude residue
was purified by column chromatography (10% EtOAc/petro-
Hz, 1H), 5.71-5.68 (m, 1H), 4.64 (s, 2H), 4.55 (dd, J = 21.3, 12.0
Hz, 2H), 3.90 (dd, J = 7.9, 4.9 Hz, 1H), 3.65 (dd, J = 10.7, 8.0 Hz,
1H), 3.39 (dd, J = 10.9, 4.8 Hz, 1H), 3.36-3.30 (m, 1H), 3.01 (br s,
1H), 2.16-2.12 (m, 1H), 2.05-2.00 (m, 2H), 1.96-1.68 (m, 4H),
1.52-1.48 (m, 2H), 1.25-1.12 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 138.9, 133.6, 128.5 (ꢀ2), 127.6 (ꢀ2), 127.5, 126.2, 96.9,
80.9, 74.9, 72.7, 70.4, 65.0, 42.4, 39.7, 36.3, 28.1, 18.8; HRMS
(ESI) m/z [M þ Na]þ, calcd for C19H26O4Na 341.1729, found
341.1729.
1-((5S,6S,8S)-8-(Benzyloxy)-1-oxaspiro[4.6]undec-3-en-6-yl)-
ethanone (27). To a magnetically stirred ice-cold solution of the
diol 26 (90 mg, 0.28 mmol) in THF/water (2:1, 3 mL) was added
NaIO4 (121 mg, 0.56 mmol) in multiple portions. The reaction
mixture was allowed to stir at 0 °C for 30 min. The precipitated
white solid was filtered off after washing it thoroughly with
diethyl ether. Usual workup of the filtrate afforded the aldehyde
(68 mg, 84%) as a colorless oil: [R]27D þ11.5 (c 0.8, CHCl3); νmax
(film) 2932, 2860, 1722, 1639, 1452 cm-1; 1H NMR (300 MHz,
CDCl3) δ 9.48 (d, J = 2.2 Hz, 1H), 7.27-7.18 (m, 5H), 5.86-
5.80 (m, 2H), 4.57-4.39 (m, 4H), 3.38-3.21 (m, 1H), 2.25-2.20
(m, 2H), 1.99-1.82 (m, 2H), 1.79-1.58 (m, 4H), 1.32-1.17
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 202.4, 138.9, 132.9,
128.5 (ꢀ2), 127.7 (ꢀ2), 127.6, 126.8, 92.8, 79.5, 75.2, 70.4, 55.0,
40.8, 35.7, 27.7, 18.8; HRMS (ESI) m/z [M þ Na]þ, calcd for
C18H22O3Na 309.1467, found 309.1466.
leum ether), to give 23 (245 mg, 65%) as a colorless liquid: [R]26
D
-2.1 (c 3.0, CHCl3); νmax (film) 3522, 2930, 2860, 1639, 1494
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.84
(dd, J = 17.0, 10.6 Hz, 1H), 5.37 (dd, J = 17.0, 1.7 Hz, 1H), 5.08
(dd, J = 10.6, 1.7 Hz, 1H), 4.56 (s, 2H), 4.41 (dt, J = 6.9, 1.7 Hz,
1H), 3.95 (dd, J = 8.0, 7.1 Hz, 1H), 3.54 (dd, J = 8.0, 6.9 Hz,
1H), 3.46-3.38 (m, 1H), 3.32 (br s, 1H), 2.21-1.80 (m, 4H),
1.77-1.47 (m, 11H), 1.43-1.35 (m, 2H), 1.32-1.20 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 145.4, 139.1, 128.5 (ꢀ2), 127.6 (ꢀ2),
127.6, 112.0, 110.3, 79.6, 77.2, 75.7, 70.4, 67.4, 42.8, 42.1, 35.9,
35.2, 34.2, 26.2, 25.2, 24.2, 24.0, 18.1; HRMS (ESI) m/z [M þ
Na]þ, calcd for C24H34O4Na 409.2355, found 409.2351.
(S)-2-((1R,2S,6S)-2-(Allyloxy)-6-(benzyloxy)-2-vinylcyclohep-
tyl)-1,4 dioxaspiro[4.5]decane (24). To a magnetically stirred
suspension of NaH (103 mg, 2.58 mmol, 60% in oil), freed from
adhering oil by repeated washing with petroleum ether, in dry
THF (7 mL) was added dropwise a solution of the alcohol 23
(250 mg, 0.65 mmol) in dry THF (3 mL) under Ar atmosphere.
The mixture was allowed to stir at reflux for 1 h, and then to it
was added TBAI (ca. 50 mg) followed by allyl bromide (0.2 mL,
2.58 mmol). After stirring for an additional 1 h at reflux, the
reaction mixture was cooled to 0 °C and quenched by adding
saturated aqueous NH4Cl solution (1 mL). Usual workup of the
reaction mixture followed by column chromatography (10%
Et2O/petroleum ether) afforded the allyl ether 24 (254 mg, 92%)
To a solution of the aldehyde (80 mg, 0.28 mmol) in dry
diethyl ether (1 mL) was added methylmagnesiumbromide
[prepared from magnesium turnings (47 mg, 1.95 mmol) in dry
diethyl ether (3 mL) and methyl iodide (0.10 mL, 1.40 mmol)] at
0 °C. The mixture was stirred at that temperature for 1 h and
quenched with saturated aqueous NH4Cl solution. After stirring
for 15 min at rt, the mixture was extracted with diethyl ether (2 ꢀ
5 mL). The combined organic layer was dried and concentrated in
vacuo. The resulting crude product was chromatographed (15%
Et2O/petroleum ether) affording the mixture of corresponding
methyl addition products (74 mg, 87%) as a colorless liquid.
as a colorless liquid: [R]28 þ20.9 (c 1.4, CHCl3); νmax (film)
D
1
2933, 2860, 1645, 1495 cm-1; H NMR (300 MHz, CDCl3) δ
7.38-7.28 (m, 5H), 5.96-5.83 (m, 1H), 5.80-5.71 (m, 1H), 5.37
(dd, J = 17.2, 1.9 Hz, 1H), 5.15-5.10 (m, 2H), 4.59 (dd, J =
16.2, 12.3 Hz, 2H), 4.36-4.30 (m, 1H), 3.98-3.92 (m, 3H), 3.45
(t, J = 8.3 Hz, 1H), 3.42-3.33 (m, 1H), 2.36 (d, J = 14.3 Hz,
1H), 2.18-2.08 (m, 1H), 2.01-1.87 (m, 3H), 1.84-1.70 (m, 2H),
1.67-1.48 (m, 10H), 1.41 (br s, 3H); 13C NMR (75 MHz,
CDCl3) δ 141.7, 139.2, 135.8, 128.4 (ꢀ2), 127.6 (ꢀ2), 127.5,
114.7, 114.1, 108.1, 80.7, 80.6, 75.5, 70.1, 69.5, 62.8, 46.7, 36.7,
36.3, 35.8, 35.5, 29.6, 25.4, 24.2, 24.1, 18.5; HRMS (ESI) m/z
[M þ Na]þ, calcd for C27H38O4Na 449.2668, found 449.2661.
(5S,6R,8S)-8-(Benzyloxy)-6-((S)-1,4-dioxaspiro[4.5]decan-2-
yl)-1-oxaspiro[4.6]undec-3-ene (25). A solution of the diene 24
(240 mg, 0.56 mmol) in anhydrous deoxygenated CH2Cl2 q(50
mL) was treated with Grubbs first generation catalyst (23 mg, 5
mol %) under argon atmosphere and stirred at rt for 3 h. The
residual mass obtained after removal of the solvent was chro-
matographed (10% Et2O/petroleum ether) to afford the spiro
compound 25 (210 mg, 94%) as a colorless liquid: [R]27D þ30.7
Major diastereoisomer: [R]29 þ2.5 (c 3.0, CHCl3); νmax (film)
D
1
3402, 2930, 1653, 1450 cm-1; H NMR (300 MHz, CDCl3) δ
7.34-7.25 (m, 5H), 5.85-5.78 (m, 2H), 4.63-4.48 (m, 4H), 3.98-
3.91 (m, 1H), 3.49-3.42 (m, 1H), 2.19 (br s, 1H), 2.05-1.99 (m,
2H), 1.95-1.78 (m, 3H), 1.73-1.60 (m, 3H), 1.32-1.23 (m, 1H),
1.17 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 139.0,
134.7, 128.3 (ꢀ2), 127.5 (ꢀ2), 127.3, 125.0, 94.0, 80.3, 73.9, 70.2,
69.5, 48.1, 40.7, 34.9, 29.0, 20.2, 18.7; HRMS (ESI) m/z [M þ
Na]þ, calcd for C19H26O3Na 325.1780, found 325.1781. Minor
diastereoisomer: [R]26 þ20.6 (c 2.4, CHCl3); νmax (film) 3387,
D
2858, 1653, 1496 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.24
(m, 5H), 5.89 (d, J = 6.1 Hz, 1H), 5.71-5.67 (m, 1H), 4.65 (s, 2H),
4.64 (d, J = 11.8 Hz, 1H), 4.53 (d, J = 12.1 Hz, 1H), 4.01(q, J =
6.4 Hz, 1H), 3.35-3.26 (m, 1H), 2.19-2.12 (m, 2H), 1.92 (m, 5H),
1.62-1.50 (m, 1H), 1.33 (d, J = 9.5 Hz, 1H), 1.12 (d, J = 6.4 Hz,
3H); 13C NMR (75MHz, CDCl3) δ 139.1, 133.9, 128.5 (ꢀ2), 127.6
(ꢀ2), 127.5, 125.9, 96.9, 81.3, 74.9, 70.3, 67.3, 46.1, 40.0, 36.5, 26.8,
20.7, 19.0; HRMS (ESI) m/z [M þ Na]þ, calcd for C19H26O3Na
325.1780, found 325.1782.
(c 1.0, CHCl3); νmax (film) 2932, 2858, 1604, 1494 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 5.81-5.78 (m,
1H), 5.69-5.65 (m, 1H), 4.65-4.51 (m, 4H), 4.10-4.04 (m, 1H),
3.87 (dd, J = 8.0, 2.1 Hz, 1H), 3.40-3.34 (m, 2H), 2.37-2.31 (m,
1H), 2.09-2.02 (m, 1H), 1.96-1.81 (m, 3H), 1.80-1.69 (m, 2H),
1.65-1.53 (m, 10H), 1.39 (br s, 2H); 13C NMR (75 MHz,
CDCl3) δ 139.2, 134.3, 128.4 (ꢀ2), 127.6 (ꢀ2), 127.4, 125.7,
108.1, 93.2, 80.2, 75.8, 74.7, 70.1, 69.2, 45.9, 40.8, 36.5, 35.8,
35.3, 29.5, 25.3, 24.1, 24.0, 18.8; HRMS (ESI) m/z [M þ Na]þ,
calcd for C25H34O4Na 421.2355, found 421.2354.
Following the procedure of oxidation, the above carbinol (50
mg, 0.16 mmol) was oxidized with DMP (84 mg, 0.20 mmol) to
afford the title compound 27 (48 mg, 98%) as a colorless liquid:
[R]26D þ38.3 (c 5.5, CHCl3); νmax (film) 2932, 2860, 1701, 1651,
1454 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.26-7.16 (m, 5H),
5.74-5.66 (m, 2H), 4.50-4.39 (m, 4H), 3.44-3.38 (m, 1H),
2.44-2.24 (m, 2H), 2.00 (s, 3H), 1.95-1.73 (m, 5H), 1.59-1.48
(m, 1H), 1.30-1.21 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 210.6, 138.8, 133.7, 128.4 (ꢀ2), 127.5 (ꢀ3), 125.5, 92.4, 78.8,
74.5, 70.4, 57.1, 41.0, 34.2, 30.5, 28.0, 18.5; HRMS (ESI) m/z
[M þ Na]þ, calcd for C19H24O3Na 323.1623, found 323.1624.
2-((5S,6R,8S)-8-(Benzyloxy)-1-oxaspiro[4.6]undec-3-en-6-yl)-
propan-2-ol (28). Following the procedure of Grignard reaction,
(S)-1-((5S,6R,8S)-8-(Benzyloxy)-1-oxaspiro[4.6]undec-3-en-
6-yl)ethane-1,2-diol (26). A mixture of the spiro-cyclic com-
pound 25 (450 mg, 1.13 mmol) and acetic acid (8 mL, 80% in
water) was stirred at rt for 17 h. The resulting solution was con-
centrated in reduced pressure. Purification of the residual mass by
column chromatography (40% EtOAc/petroleum ether) afforded
diol 26 (295 mg, 82%) as a colorless oil: [R]27 þ12.7 (c 5.9,
D
CHCl3); νmax (film) 3435, 2933, 2860, 1641, 1496, 1454 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.34-7.25 (m, 5H), 5.90 (d, J = 6.1
4198 J. Org. Chem. Vol. 75, No. 12, 2010

Maity et al.
JOCArticle
the methyl ketone 27 (100 mg, 0.33 mmol) was reacted with
MeMgI to afford the carbinol 28 (95 mg, 90%) as a colorless
liquid: [R]27D -6.7 (c 1.2, CHCl3); νmax (film) 3466, 2930, 2860,
1496, 1454 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m,
5H), 6.04 (td, J = 6.2, 2.4 Hz, 1H), 5.74 (td, J = 6.2, 1.5 Hz, 1H),
4.65 (t, J = 2.0 Hz, 2H), 4.58 (dd, J = 20.0, 12.1 Hz, 2H), 3.46-
3.36 (m, 1H), 2.12-1.90 (m, 5H), 1.76-1.56 (m, 5H), 1.27 (s,
3H), 1.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.1, 138.0,
128.5 (ꢀ2), 127.6 (ꢀ2), 127.5, 123.3, 95.2, 80.3, 74.8, 73.3, 70.3,
50.3, 41.8, 35.6, 31.9, 30.5, 27.8, 19.2; HRMS (ESI) m/z [M þ
Na]þ, calcd for C20H28O3Na 339.1936, found 339.1939.
19.1; HRMS (ESI) m/z [M þ Na]þ, calcd for C20H24O5Na
367.1521, found 367.1522.
Synthesis of 33. To a solution of substrate 28 (30 mg, 0.09
mmol) in acetone (1 mL) was added 0.2 mL of a premix solution
[chromium trioxide (540 mg, 5.40 mmol) in water (1.3 mL) and
2 drops of conc H2SO4]. The reaction was stirred at 50 °C for 1 h
before being quenched by addition of brine (0.1 mL). The
solution was then extracted with CH2Cl2 (3 ꢀ 5 mL). The
combined organics were dried over Na2SO4, filtered, and eva-
porated in vacuo to give the crude product. Flash chromato-
graphy (30% Et2O/petroleum ether) afforded the lactone 33 (23
mg, 72%) as a crystalline solid: mp 135-137 °C; [R]28D -21.7 (c
0.6, CHCl3); νmax (KBr plate) 2976, 2933, 1768, 1494, 1456
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.24 (m, 5H), 4.54
(dd, J = 19.0, 12.0 Hz, 2H), 4.34 (d, J = 5.1 Hz, 1H), 3.62-3.56
(m, 1H), 2.74 (dd, J = 18.4, 5.2 Hz, 1H), 2.62 (d, J = 18.4 Hz,
1H), 1.99-1.84 (m, 6H), 1.68-1.57 (m, 3H), 1.26 (s, 3H), 1.11 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 175.5, 139.0, 128.5 (ꢀ2),
127.6, 127.5 (ꢀ2), 97.4, 85.3, 82.0, 78.3, 70.3, 51.7, 38.3, 36.7,
32.2, 29.8, 29.6, 24.7, 19.0; HRMS (ESI) m/z [M þ Na]þ, calcd
for C20H26O4Na 353.1729, found 353.1726.
Synthesis of 29. N-Bromosuccinimide (78 mg, 0.44 mmol) was
added to a solution of 28 (70 mg, 0.22 mmol) in DMSO (2 mL).
After stirring for 1 h, the reaction was quenched by addition of
10% aqueous Na2S2O3 solution (0.3 mL) and then concentrated in
vacuo. The residue was partitioned between diethyl ether (10 mL)
and water (2 mL), the phases were separated, and the aqueous
layer was further extracted with diethyl ether (2 ꢀ 5 mL). The
combined organic extracts were dried and concentrated in vacuo.
Purification of the residual mass by column chromatography
(7% Et2O/petroleum ether) afforded 29 (86 mg, 98%) as crystal-
line solid: mp 133-135 °C; [R]26 -32.6 (c 1.20, CHCl3); νmax
Synthesis of 34. A solution of compound 30 (20 mg, 0.06
mmol) in dry methanol (2 mL) containing Pd-C (10%) was
stirred under hydrogen atmosphere at room temperature for
15 h. The catalyst was filtered off, and removal of solvent in
vacuo afforded the alcohol 34 (13 mg, 91%) as a colorless liquid:
[R]27D -14.1 (c 5.0, CHCl3); νmax (liquid film) 3420, 2930, 2880,
1454 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.24 (dd, J=5, 1.5
Hz, 1H), 4.09 (dd, J=16.0, 8.0 Hz, 1H), 4.01-3.97 (m, 1H), 3.94
(dt, J=8.5, 5.0 Hz, 1H), 2.51 (br s, 1H), 2.09-1.96 (m, 4H),
1.90-1.79 (m, 3H), 1.75 (td, J=14.0, 4.5 Hz, 1H), 1.67-1.62 (m,
1H), 1.55-1.50 (m, 1H), 1.44-1.38 (m, 1H), 1.21 (s, 3H), 1.17 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 95.4, 86.8, 84.9, 69.7, 67.6,
53.9, 36.3, 34.2, 33.6, 33.4, 30.3, 24.7, 18.0; HRMS (ESI) m/z
[M þ Na]þ, calcd for C13H22O3Na 249.1467, found 249.1467.
Synthesis of 35. Following the above methods of RuO4
mediated oxidation, the compound 34 (10 mg, 0.04 mmol) was
transformed into lactone 35 (9 mg, 85%) as a crystalline solid:
mp 174-175 °C; [R]28D -134.0 (c 2.6, CHCl3); νmax (KBr plate)
D
(KBr plate) 2937, 2868, 1452, 1363 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.35-7.25 (m, 5H), 4.60-4.48 (m, 3H), 4.44 (d, J =
0.9 Hz, 1H), 4.22 (dt, J = 6.4, 1.4 Hz, 1H), 4.13 (dd, J = 10.5, 5.2
Hz, 1H), 3.57-3.48 (m, 1H), 2.32-2.23 (m, 1H), 2.06-1.74 (m,
6H), 1.60-1.43 (m, 2H), 1.21 (s, 3H), 1.15 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 139.1, 128.5 (ꢀ2), 127.6 (ꢀ2), 127.5, 95.8,
94.4, 85.8, 79.0, 75.4, 70.3, 52.4, 50.6, 35.8, 32.0, 30.0, 29.7, 24.0,
19.6; HRMS (ESI) m/z [M þ Na]þ, calcd for C20H27BrO3Na
417.1041, found 417.1042.
Synthesis of 30. Tributyltin hydride (41 μL, 0.15 mmol) was
added to a degassed solution of 29 (50 mg, 0.13 mmol) and
catalytic AIBN in benzene (5 mL), and the resultant solution
was refluxed for 2 h. On cooling, the reaction was quenched via
the addition of carbon tetrachloride (0.5 mL), and the flask
contents were concentrated in vacuo. The residue was taken
up in ethyl acetate (10 mL), and saturated aqueous KF solu-
tion (5 mL) was added and stirred vigorously for 30 min. The
flask contents were filtered through Celite, the aqueous layer
was separated and further extracted with ethyl acetate (2 ꢀ 5
mL) and the combined organic extracts were dried and con-
centrated in vacuo. Column chromatography (10% Et2O/petro-
leum ether) afforded 30 (39 mg, 96%) as a colorless liquid:
2974, 2930, 1769, 1695 cm-1; H NMR (500 MHz, CDCl3) δ
1
4.47 (d, J = 5.5 Hz, 1H), 2.85-2.78 (m, 2H), 2.71-2.65 (m, 2H),
2.62-2.56 (m, 1H), 2.37-2.31 (m, 2H), 2.07-2.03 (m, 1H),
2.00-1.94 (m, 1H), 1.93-1.87 (m, 1H), 1.76 (dt, J = 13.5, 3.5
Hz, 1H), 1.31 (s, 3H), 1.11 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 210.2, 174.9, 96.1, 85.1, 81.2, 51.1, 44.1, 38.7, 38.0, 37.9, 29.7,
24.7, 19.3; HRMS (ESI) m/z [M þ Na]þ, calcd for C13H18O4Na
261.1103, found 261.1105.
[R]26 þ0.4 (c 4.3, CHCl3); νmax (liquid film) 2932, 2876,
D
1452 cm-1 1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m,
;
5H), 4.55 (dd, J = 17.9, 12.0 Hz, 2H), 4.22 (dd, J = 4.2, 1.8
Hz, 1H), 4.06 (dd, J = 16.0, 8.1 Hz, 1H), 4.00-3.92 (m, 1H),
3.59-3.50 (m, 1H), 2.08-1.93 (m, 4H), 1.90-1.69 (m, 5H),
1.53-1.37 (m, 2H), 1.23 (s, 3H), 1.17 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 139.3, 128.4 (ꢀ2), 127.6 (ꢀ2), 127.5, 94.6, 87.1,
84.6, 79.0, 70.2, 67.1, 52.2, 35.7, 33.6, 32.5, 30.2, 30.1, 24.0, 19.4;
HRMS (ESI) m/z [M þ Na]þ, calcd for C20H28O3Na 339.1936,
found 339.1935.
1-((5S,6S,8S)-8-(Benzyloxy)-1-oxaspiro[4.6]undec-3-en-6-yl)-
2-(tert-butyldimethylsilyloxy)ethanone (36). To a magnetically
stirred suspension of NaH (50 mg, 1.25 mmol, 60% in oil), freed
from adhering oil by repeated washing with petroleum ether, in
dry THF (3 mL) was added dropwise a solution of the alcohol 26
(100 mg, 0.32 mmol) in dry THF (1 mL) under Ar atmosphere.
The mixture was allowed to stir at rt for 1 h, and then to it was
added TBSCl (71 mg, 0.47 mmol). After stirring overnight, the
reaction mixture was cooled to 0 °C and quenched by adding
saturated aqueous NH4Cl solution (0.5 mL). Usual workup of
the reaction mixture followed by column chromatography (10%
Et2O/petroleum ether) afforded the silyl ether (122 mg, 90%) as
a colorless liquid: [R]26D þ3.7 (c 1.2, CHCl3); νmax (film) 3481,
Synthesis of 31. A mixture of 30 (6 mg, 0.02 mmol), ruthenium
trichloride (5 mg, 0.02 mmol), and sodium metaperiodate (40
mg, 0.19 mmol) in 2:2:1 CH3CN/CCl4/H2O (1 mL) was stirred
for 5 h, diluted with CH2Cl2 (5 mL), dried, and filtered. After
solvent evaporation, the residue was subjected to flash chroma-
tography (30% Et2O/petroleum ether) to afford 31 (5 mg, 76%)
as a colorless oil: [R]26D -18.8 (c 0.4, CHCl3); νmax (liquid film)
2930, 2856, 1776, 1712, 1452 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.06 (dd, J = 8.1, 1.0 Hz, 2H), 7.59-7.53 (m, 1H), 7.47-7.42
(m, 2H), 5.26-5.20 (m, 1H), 4.40 (d, J = 5.2 Hz, 1H), 2.78 (dd,
J = 18.4, 5.3 Hz, 1H), 2.65 (d, J = 18.4 Hz, 1H), 2.24-1.90 (m,
7H), 1.80-1.66 (m, 2H), 1.31 (s, 3H), 1.11 (s, 3H); 13C NMR (75
MHz, CDCl3) δ175.5, 166.1, 133.1, 130.6, 129.8 (ꢀ2), 128.5
(ꢀ2), 97.4, 85.3, 82.1, 74.0, 51.5, 38.3, 36.6, 32.7, 29.8, 29.0, 24.7,
2954, 1643, 1463 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.34-7.27 (m, 5H), 5.89 (d, J = 6.2 Hz, 1H), 5.70-5.68 (m,
1H), 4.65 (br s, 2H), 4.60 (d, J = 11.9 Hz, 1H), 4.50 (d, J = 11.9
Hz, 1H), 3.84 (dd, J = 8.9, 5.4 Hz, 1H), 3.61 (dd, J = 9.9, 5.4 Hz,
1H), 3.47 (t, J = 9.4 Hz, 1H), 3.41-3.32 (m, 1H), 2.18-2.04 (m,
2H), 1.96-1.71 (m, 6H), 1.59-1.46 (m, 1H), 1.27-1.15 (m, 1H),
0.87 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 139.1,
134.0, 128.5 (ꢀ2), 127.7 (ꢀ2), 127.5, 125.8, 97.2, 81.4, 74.8, 72.3,
J. Org. Chem. Vol. 75, No. 12, 2010 4199

Maity et al.
JOCArticle
70.5, 63.4, 40.6, 40.2, 36.5, 26.8, 26.0 (ꢀ3), 19.0, 18.3, -5.1,
-5.2; HRMS (ESI) m/z [M þ Na]þ, calcd for C25H40O4SiNa
455.2594, found 455.2592.
cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.28-7.21 (m, 5H),
4.56-4.52 (m, 1H), 4.50 (d, J = 12.0 Hz, 1H), 4.45 (d, J =
12.0 Hz, 1H), 4.32 (s, 1H), 4.21-4.14 (m, 2H), 3.47-3.45 (m,
1H), 3.35 (d, J=10.5 Hz, 1H), 3.26 (d, J=10.5 Hz, 1H), 2.30-
2.25 (m, 1H), 2.23 (d, J=12.5 Hz, 1H), 2.00-1.82 (m, 3H), 1.83-
1.75 (m, 2H), 1.58-1.53 (m, 1H), 1.46-1.42 (m, 1H), 1.01 (s,
3H), 0.85 (s, 9H), 0.00 (d, J = 4.0 Hz, 6H); 13C NMR (125 MHz,
CDCl3) δ 139.2, 128.4 (ꢀ2), 127.6 (ꢀ2), 127.5, 96.2, 94.0, 87.4,
79.1, 76.0, 70.3, 69.5, 50.5, 46.0, 36.4, 32.3, 30.0, 26.0 (ꢀ3), 19.8,
19.7, 18.3, -5.2, -5.4; HRMS (ESI) m/z [M þ Na]þ, calcd for
C26H41BrO4SiNa 547.1855, found 547.1851.
Following the procedure of oxidation, the above carbinol
(140 mg, 0.32 mmol) was oxidized with DMP (178 mg, 0.42
mmol) to afford the title compound 36 (132 mg, 95%) as a
colorless liquid: [R]26 þ14.0 (c 2.2, CHCl3); νmax (film) 2930,
D
2856, 1717, 1497 cm-1; H NMR (300 MHz, CDCl3) δ 7.25-
1
7.17 (m, 5H), 5.78-5.72 (m, 2H), 4.54-4.39 (m, 4H), 4.15 (d,
J = 17.7 Hz, 1H), 4.01 (d, J = 17.7 Hz, 1H), 3.45-3.37 (m, 1H),
2.93 (d, J = 9.9 Hz, 1H), 2.34-2.24 (m, 1H), 1.98-1.74 (m, 5H),
1.60-1.54 (m, 1H), 1.34-1.27 (m, 1H), 0.85 (s, 9H), 0.01 (d, J =
4.5 Hz, 6H); ; 13C NMR (75 MHz, CDCl3) δ 210.8, 139.0, 133.5,
128.5 (ꢀ2), 127.6 (ꢀ2), 127.5, 126.1, 92.1, 78.5, 74.8, 70.2, 68.8,
51.1, 41.2, 34.4, 30.0, 26.0 (ꢀ3), 18.7, 18.5, -5.3 (ꢀ2); HRMS
(ESI) m/z [M þ Na]þ, calcd for C25H38O4SiNa 453.2437, found
453.2435.
Synthesis of 40 and 41. Following the above methods of
reductive removal of bromide followed by RuO4 mediated
oxidation, the compound 38 (12 mg, 0.02 mmol) was trans-
formed into lactone 40 (8 mg, 74%) and 39 (10 mg, 0.02 mmol)
to 41 (6.5 mg, 72%). Compound 40: [R]28D -22.0 (c 0.3, CHCl3);
ν
max (liquid film) 2928, 2855, 1778, 1712, 1454 cm-1; 1H NMR
(500 MHz, CDCl3) δ 8.04 (dd, J = 7.0, 1.0 Hz, 2H), 7.55 (t, J =
7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 5.17-5.15 (m, 1H), 4.40 (d,
J = 5.0 Hz, 1H), 3.55 (d, J = 10.0 Hz, 1H), 3.34 (d, J = 10.0 Hz,
1H), 2.75 (dd, J = 18.5, 5.0 Hz, 1H), 2.64 (d, J = 18.5 Hz, 1H),
2.39-2.36 (m, 1H), 2.18-1.90 (m, 6H), 1.77-1.73 (m, 2H), 1.33
(s, 3H), 0.82 (s, 9H), 0.00 (d, J = 2.5 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ175.2, 166.0, 133.0, 130.7, 129.8 (ꢀ2), 128.5
(ꢀ2), 97.1, 86.8, 82.5, 74.5, 66.8, 51.8, 38.0, 36.0, 32.3, 28.2, 26.0
(ꢀ3), 25.1, 19.3, 18.3, -5.5 (ꢀ2); HRMS (ESI) m/z [M þ Na]þ,
calcd for C26H38O6SiNa 497.2336, found 497.2337. Compound
2-((5S,6R,8S)-8-(Benzyloxy)-1-oxaspiro[4.6]undec-3-en-6-yl)-
1-(tert-butyldimethylsilyloxy)propan-2-ol (37). Following the pro-
cedure of Grignard reaction, the ketone 36 (85 mg, 0.20 mmol)
was reacted with MeMgI to afford the mixture of carbinols
37 (95 mg, 90%) in a ca. 3:2 ratio. [R]26 þ3.2 (c 3.0, CHCl3);
D
1
νmax (film) 3558, 3485, 2928, 2856, 1496 cm-1; H NMR (300
MHz, CDCl3) δ 7.28-7.15 (m, 5H), 5.97-5.86 (m, 1H), 5.58-
5.54 (m, 1H), 4.55-4.42 (m, 4H), 3.41 (br s, 2H), 3.39-3.33 (m,
1H), 2.78 (br s, 1H), 2.23 (dd, J = 6.4, 2.8 Hz, 1H), 1.96-1.88
(m, 2H), 1.87-1.75 (m, 2H), 1.74-1.48 (m, 3H), 1.22-1.17 (m,
1H), 1.08 and 1.06 (both s, total 3H), 0.82 (s, 9H), -0.03 (s, 6H);
13C NMR (75 MHz, CDCl3) δ (for major isomer) 139.3,
137.8, 128.4 (ꢀ2),127.6 (ꢀ2), 127.4, 122.7, 94.1, 81.2, 76.2,
73.5, 70.3, 69.5, 46.4, 42.7, 35.5, 29.5, 26.0 (ꢀ3), 22.7, 19.0,
18.4, -5.2, -5.3, (for minor isomer) 139.2, 138.1, 128.4 (ꢀ2),
127.5 (ꢀ2), 127.4, 121.8, 94.7, 80.5, 76.2, 73.3, 70.3, 69.3, 45.2,
42.8, 35.1, 30.1, 26.0 (ꢀ3), 23.3, 19.0, 18.4, -5.2, -5.3; HRMS
(ESI) m/z [M þ Na]þ, calcd for C26H42O4SiNa 469.2750, found
469.2754.
41: [R]23 -26.9 (c 0.3, CHCl3); νmax (film) 2951, 2857, 1782,
D
1715, 1452 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J =
8.0, 1.0 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz,
2H), 5.26-5.21 (m, 1H), 4.34 (d, J = 3.5 Hz, 1H), 3.49 (d, J =
11.0 Hz, 1H), 3.38 (d, J = 11.0 Hz, 1H), 2.71 (d, J = 4.0 Hz, 1H),
2.70 (s, 1H), 2.59 (dd, J = 12.5, 2.0 Hz, 1H), 2.19-2.10 (m, 2H),
2.03-1.88 (m, 4H), 1.74-1.68 (m, 2H), 1.03 (s, 3H), 0.91 (s, 9H),
0.06 (d, J = 3.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 175.4,
166.0, 133.1, 130.7, 129.8 (ꢀ2), 128.5 (ꢀ2), 97.7, 87.3, 82.7, 74.0,
68.7, 44.2, 38.2, 36.0, 32.8, 29.0, 26.0 (ꢀ3), 20.4, 19.1, 18.3, -5.2,
-5.3; HRMS (ESI) m/z [M þ Na]þ, calcd for C26H38O6SiNa
497.2336, found 497.2333.
Synthesis of 38 and 39. Following the method of bromonium-
ion mediated cyclization, the above mixture of carbinols 37 (55
mg, 0.12 mmol) was cyclized with NBS (28 mg, 0.16 mmol) to
afford after column chromatography, the bromo bis-tetrahy-
drofuran derivative 38 (35 mg, 54%) and 39 (20 mg, 32%) as a
Acknowledgment. Financial support from Department of
Science and Technology, Government of India through a
Ramanna Fellowship to S.G. is gratefully acknowledged.
S.M. and K.M. thank CSIR, New Delhi for SRF and
Tanurima Bhaumik for valuable suggestions. Financial
support from DST for the National Single Crystal X-ray
Diffractometer facility at the Department of Inorganic
Chemistry is gratefully acknowledged.
colorless liquid. Compound 38: [R]27 -13.0 (c 3.5, CHCl3);
D
νmax (film) 2930, 2858, 1454, 1362 cm-1; 1H NMR (500 MHz,
CDCl3) δ 7.28-7.20 (m, 5H), 4.52-4.48 (m, 3H), 4.41 (s, 1H),
4.14 (t, J = 5.5 Hz, 1H), 4.09 (dd, J = 10.5, 5.0 Hz, 1H), 3.58 (d,
J = 10.0 Hz, 1H), 3.44-3.42 (m, 1H), 3.41 (d, J = 9.5 Hz, 1H),
2.25-2.21 (m, 1H), 2.14-2.11 (m, 1H), 1.97-1.93 (m, 1H),
1.91-1.80 (m, 3H), 1.79-1.72 (m, 1H), 1.51-1.42 (m, 2H), 1.24
(s, 3H), 0.85 (s, 9H), 0.03 (d, J = 4.0 Hz, 6H); 13C NMR (125
MHz, CDCl3) δ 139.2, 128.4 (ꢀ2), 127.5 (ꢀ2), 127.5, 95.6, 94.5,
87.1, 78.9, 75.5, 70.2, 66.2, 52.6, 50.1, 35.4, 32.3, 28.0, 26.1 (ꢀ3),
24.8, 19.5, 18.4, -5.3, -5.4; HRMS (ESI) m/z [M þ Na]þ, calcd
for C26H41BrO4SiNa 549.1839, found 549.1836. Compound 39:
[R]27D -32.1 (c 1.6, CHCl3); νmax (film) 2951, 2862, 1456, 1363
Supporting Information Available: General experimental
methods along with copies of NMR spectra and X-ray crystal
data with ORTEP plot. This material is available free of charge
via the Internet at http://pubs.acs.org.
4200 J. Org. Chem. Vol. 75, No. 12, 2010