A stereocontrolled entry to 3-functionalized cis-3a-methyloctahydroindoles: Building blocks for Daphniphyllum alkaloid synthesis

Article abstract of DOI:10.1055/s-2007-986633

A synthetic entry to cis-3a-methyl-3-methyleneoctahydroindol-5-ones employing ozonolysis, chemoselective methylenation, and double reductive amination of 2-(1-formylvinyl)-2-methyl-1,4-cyclohexanedione monoethylene acetal is described. The same process us

Full text of DOI:10.1055/s-2007-986633

LETTER
2379
A Stereocontrolled Entry to 3-Functionalized cis-3a-Methyloctahydroindoles:
Building Blocks for Daphniphyllum Alkaloid Synthesis
S
ynthesis of cis-3a
l
-Methy
e
l-3-methyl
j
eneocta
a
hydroindol
n
-5-one
D
eriv
d
atives ro Cordero-Vargas, Xavier Urbaneja, Josep Bonjoch*
Laboratorio de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax +34(93)4024539; E-mail: josep.bonjoch@ub.edu
Received 15 May 2007
Abstract: A synthetic entry to cis-3a-methyl-3-methyleneoctahy-
H
N
H
N
O
droindol-5-ones employing ozonolysis, chemoselective methylena-
tion, and double reductive amination of 2-(1-formylvinyl)-2-
methyl-1,4-cyclohexanedione monoethylene acetal is described.
The same process using a 2-methoxycarbonyl derivative gave a
trans-diastereoselectivity in the formation of the azabicyclic com-
pound. Diastereoselective hydroboration of the exocyclic methyl-
ene of cis-octahydroindole derivative gives a valuable synthetic
intermediate for Daphniphyllum alkaloid synthesis.
Me
Me
Me
Me
O
H
O
CO2Me
daphniyunnine A
dendrobine
Figure 1
Key words: alkenation, aminations, fused-ring systems, ring clo-
sure, stereoselectivity
Bn
H
O
O
N
O
TMS
Functionalized cis-3a-methyloctahydroindoles are a key
architectural feature in a wide array of Daphniphyllum
alkaloids1 as well as dendrobine-type alkaloids2
(Figure 1). Our interest in Daphniphyllum alkaloids3 with
the hexacyclic ring of daphniyunnine A,4 its N-oxide
calyciphilline A5 and related congeners6 has directed our
attention to the synthesis of 3-functionalized cis-3a-meth-
yloctahydroindoles with a trans-relationship between the
substituent at C-3 and the methyl group at C-3a. Our ap-
proach to the synthesis of these building blocks involves
the preparation of a 3-methylene derivative, which could
then give access to several functionalities (Scheme 1) to
be used in synthetic approaches to the aforementioned
natural products embodying this structural motif.
R
ref. 7
O
Cp2ZrBu
this work
Ts
PG
H
N
N
ref. 8
MeO
R
PtCl2, MeOH
Bn
H
N
ref. 9
Ts
N
R'
Me
W(CO)6, hν
As envisioned in Scheme 1, cis-3-methylene-3a-alkyl-
octahydroindoles have been previously obtained by
formation of the C-3–C-3a bond from 2-alkenyl N-prop-
argylaminocyclohexanes through a cyclization catalyzed
by transition metals [Zr(II),7 Pt(II),8 or W(0)9].10 In this
letter, we report a different approach based on the inter-
and intramolecular double reductive amination of a-(1-
formylvinyl)cyclohexanones. This procedure allows the
incorporation of additional functionalization at the car-
bocyclic ring to gain access to cis-3-methylene-3a-meth-
yloctahydroindol-5-one derivatives, which could be
considered valuable intermediates in the Daphniphyllum
alkaloid synthesis, particularly if the methylene group
could be stereoselectively transformed into a functional-
ized appendage at C-3 with the same relative configura-
tion as that of the natural products.
THF
O
O
TIPSO
Scheme 1 Synthetic approaches to cis-3-methylene-3a-methylocta-
hydroindoles
The starting material for the synthetic entry to our aza-
bicyclic target was ketone 1 (Scheme 2), which was
prepared from the monoethylene acetal of 1,4-cyclohex-
anedione by a-methylation (LiHMDS, MeI, THF, 70%)11
followed by regioselective allylation under thermody-
namic conditions using sodium hydride as the base (NaH,
BrCH2CH=CH2, NaI, THF, r.t., 66%). This alternative to
our previously reported procedure3 for the a,a-disubstitut-
ed cylohexanedione 1,12 although giving a lower overall
yield, requires only two steps instead of five. Ketone 1
was submitted to a one-pot procedure reductive ozonoly-
sis–methylenation process, using the protocol developed
by Hon13 (CH2Br2–Et3N) in the second step, giving keto
aldehyde 2 in 42% yield.14,15 The double reductive
SYNLETT 2007, No. 15, pp 2379–2382
1
7
.0
9
.2
0
0
7
Advanced online publication: 28.08.2007
DOI: 10.1055/s-2007-986633; Art ID: D14807ST
© Georg Thieme Verlag Stuttgart · New York

2380
A. Cordero-Vargas et al.
LETTER
Bn
Bn
H
O
CHO
O
N
N
BH3⋅THF
H
BnNH2⋅HCl
MeOH, r.t.
HO
1) O3, CH2Cl2
–78 °C
THF, r.t.
Me
Me
Me
Me
then H2O2, aq NaOH
2) CH2Br2, Et2NH
CH2Cl2
–78 °C to r.t.
O
O
O
O
O
O
O
O
1
3 (60%)
4 (76%)
2 (42%)
Scheme 2 Stereoselective synthesis of 3-hydroxymethyl-3a-methyloctahydroindolone 4
amination of 2 using benzylamine hydrochloride and The relative stereochemistry of 3 and 10 was elucidated
sodium cyanoborohydride diastereoselectively furnished by 2D NMR spectra (COSY and HSQC). The key evi-
cis-octahydroindole 3 in 60% overall yield.16,17 Diastereo- dence for the stereochemical and, in the cis-series, confor-
selective hydroboration of 3 allowed alcohol 4 to be ob- mational elucidation of these octahydroindoles was found
tained with the desired relative configuration at the three in the 1H NMR coupling pattern for the methine proton at
stereogenic centers.18 The synthetic sequence herein C-7a, which appears as a triplet (J = 2.7 Hz) for the cis-
described is the first for octahydroindole derivatives with isomer 3 and a doublet of doublets (J = 11.9 and 3.4 Hz)
this stereochemical arrangement and tetrasubstitution for the trans-isomer. The chemical shifts of C-6 and C-7a
pattern of great interest for the development of a are of diagnostic value for the assignment of cis/trans
Daphniphyllum synthetic approach.
configuration in this series of compounds, their signals
appearing deshielded (d = 34.6 and 71.8 ppm for 10) in the
trans-series compared with the cis-derivatives (d = 28.6
and 67.8 ppm for 3).
This promising result prompted us to extend the method-
ology to the synthesis of compounds embodying a differ-
ent substituent at C-3a. Under the same reaction
conditions used for the aminocyclization of 2, keto alde- The results reported here constitute an example of the
hyde 6 did not give a cis-octahydroindole, the trans-oc- influence of the substituent at C-3a on the iminium salt
tahydroindole 7 being formed instead (Scheme 3). For reduction process in 3a-substituted hexahydro-2H-
conclusive evidence of the structural assignment, ester 7 indoles.21 The diastereoselectivity observed could be
was reduced to alcohol 8,19 which in turn was reduced
explained by the different conformational behavior of
bicyclic iminium intermediates 2A and 6A (Scheme 4),
again to give the 3a-methyl derivative 10,20 epimer of 3.
This result shows that the methyl- and methoxycarbonyl-
substituted derivatives behave differently, probably due to
a different preferred conformation of the bicyclic iminium
salt intermediates (see below).
formed when keto aldehydes 2 and 6 were submitted to
the double reductive amination.22 Thus, in order to avoid
the steric crowding between the C-3a–Me and C-5–O
bond of the acetal group, as well as to diminish the A1,3
strain between the exocyclic methylene at C-3 and the
methylene at C-4, compound 2A could adopt a conforma-
tion in which the B ring is located below the quasiplanar
ring A, implying that the acetal group blocks the bottom
face of 2a. Consequently, the hydride approach takes
place from the top face, giving the reduced compound 3
with a cis-diastereoselectivity (Scheme 4). In contrast, the
methoxycarbonyl group at C-3a in 6A is less sterically de-
manding, allowing a conformation with the acetal group
located above. The hydride attack thus occurs from the
more accessible bottom face and the resulting reduced oc-
tahydroindole 7 has a trans-relationship in the azabicyclic
ring. Although electronic effects, as observed by Woerpel
in oxacarbenium ions,23 cannot be discarded when trying
to understand the stereoselectivity in the reduction involv-
ing a cyclic iminium ion bearing an electron-withdrawing
substituent such as the methoxycarbonyl group, it should
be mentioned that in our previous study3 a cis-diastereo-
selectivity was found in the octahydroindole ring forma-
tion from 5, which lacks the methylene group.
CHO
O
O
1) O3, CH2Cl2
–78 °C
MeO2C
MeO2C
2) CH2Br2, Et2NH
CH2Cl2
–78 °C to r.t.
O
O
O
O
5
6 (64%)
Bn
Bn
N
N
H
H
LiAlH4
BnNH2⋅HCl
MeOH, r.t.
MeO2C
THF, –40 °C
OH
O
O
O
O
7 (42%)
8 (66%)
Bn
Bn
N
N
H
H
TsCl
NaBH4
Et3N, DMAP
CH2Cl2
DMSO, 90 °C
OTs
O
O
O
O
In summary, the synthesis of cis-3a-methyl-3-methyl-
eneoctahydroindol-5-one derivative 3 and alcohol 4, bear-
ing the same relative configuration in its three stereogenic
centers as daphniyunnine A, has been reported. The
9 (85%)
10 (57%)
Scheme 3 Synthesis of trans-3-methylene-3a-methyloctahydro-
indoles
Synlett 2007, No. 15, 2379–2382 © Thieme Stuttgart · New York

LETTER
Synthesis of cis-3a-Methyl-3-methyleneoctahydroindol-5-one Derivatives
2381
(11) Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y.-M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1016.
(12) For the enantioselective synthesis of 1, see: (a) Behenna, D.
C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(b) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M.
Angew. Chem. Int. Ed. 2005, 44, 6924.
(13) Hon, Y.-S.; Chang, F.-J.; Liu, L.; Lin, W.-C. Tetrahedron
1998, 54, 5233.
(14) This was higher than the 30% yield obtained when the
intermediate aldehyde was submitted to methylenation with
the Eschenmoser reagent.
CO2Me
Me
O
O
CH2
CH2
O
O
CHO
CHO
O
O
6
2
H _
CO2Me
O
CH2
N +
O
O
N+
Ph
O
Ph
2A
6A
H_
(15) 2-[(1-Methylene)formylmethyl]-2-methylcyclohexane-
1,4-dione Monoethylene Acetal (2)
conformational
change
A stirred solution of ketone 1 (1.1 g, 5.23 mmol) in CH2Cl2
(105 mL) at –78 °C was treated with a constant stream of
ozone. When the solution turned a characteristic pale blue, it
was purged with oxygen. To this solution (at –78 °C) was
added a mixture of CH2Br2 (1.84 mL, 4.54 g, 26.15 mmol)
and Et2NH (8.15 mL, 5.74 g, 78.47 mmol; preheated to 55 °C
for 1.5 h and then cooled to r.t.) and the resulting yellow
solution was stirred at r.t. for 2.5 h. The reaction mixture was
concentrated, Et2O was added (most of the ammonium salts
precipitated), and the mixture was filtered and washed with
Et2O. The residue was purified by flash column
Me
O
CO2Me
CH2
CH2
O
O
H
O
N
Ph
N
H
3
Ph
7
Scheme 4 Reaction pathways for the reduction of N-benzylhexahy-
droindole iminium salts
chromatography (silica gel, hexane–EtOAc, 2:1 to 1:1) to
give aldehyde 2 (42% yield) as a colorless oil: 1H NMR (300
MHz, CDCl3): d = 1.44 (s, 3 H, CH3), 1.62 (dd, J = 13.9, 2.9
Hz, 1 H, H-3), 2.00 (dm, J = 12.8 Hz, 1 H, H-5eq), 2.32 (td,
1 H, J = 12.8, 5.1 Hz, H-5ax), 2.42 (d, J = 13.9 Hz, 1 H, H-
3), 2.59 (dt, J = 16.5, 4.8 Hz, 1 H, H-6eq), 2.75 (ddd,
J = 16.6, 12.4, 5.7 Hz, 1 H, H-6ax), 4.05–3.91 (m, 4 H,
OCH2), 6.16 (s, 1 H, =CH), 6.35 (s, 1 H, =CH), 9.46 (s, 1 H,
CHO). 13C NMR (75 MHz, CDCl3): d = 23.5 (Me), 32.8 (C-
5), 35.9 (C-6), 43.7 (C-3), 49.5 (C-2), 64.2 and 64.6 (OCH2),
107.4 (C-4), 134.8 (=CH2), 140.3 (=C), 193.3 (CHO), 211.1
(C-1). IR (NaCl, neat): 2969, 2888, 1711, 1688, 1282, 1114,
1072, 1036 cm–1.
usefulness of these new building blocks in the total
synthesis of Daphniphyllum alkaloids is currently being
studied.
Acknowledgment
This research was supported by the MEC (Spain)-FEDER through
project CTQ2004-04701/BQU. Thanks are also due to the DURSI
(Catalonia) for Grant 2005SGR-00442 and the Ministry of Educati-
on and Science (Spain) for a fellowship to A.C.
(16) cis-1-Benzyl-3a-methyl-3-methyleneoctahydroindol-5-
one Ethylene Acetal (3)
References and Notes
To a solution of aldehyde 2 (0.4 g, 1.78 mmol) in MeOH (9
mL) were added first benzylamine hydrochloride (1.13 g,
7.85 mmol) and then NaBH3CN (0.09 g, 1.43 mmol). After
stirring for 30 min, an additional portion of NaBH3CN (0.09
g, 1.43 mmol) was added and stirring was continued for 1 h.
A third portion of NaBH3CN (0.25 g, 3.92 mmol) was then
added, and stirring was continued overnight. After removing
the MeOH, CH2Cl2 was added and the resulting organic
solution was washed with sat. aq NaHCO3 solution, dried
and concentrated. The resulting mixture was purified by
column chromatography (silica gel, hexane–EtOAc, 4:1 to
2:1) to give amine 3 (60% yield) as a yellow oil: 1H NMR
(300 MHz, CDCl3, gCOSY): d = 1.21 (s, 3 H, H-9), 1.35 (dd,
J = 13.7, 2.5 Hz, 1 H, H-4), 1.46 (ddd, J = 12.5, 6.0, 2.9 Hz,
1 H, H-7), 1.77–2.10 (m, 4 H, H-4, H-6, and H-7), 2.23 (t,
J = 2.7 Hz, 1 H, H-7a), 2.79 (dt, J = 13.7, 2.5 Hz, 1 H, H-2),
3.02 (d, J = 13.2 Hz, 1 H, CH2Ph), 3.64 (dt, J = 14.5, 1.8 Hz,
1 H, H-2), 3.88–4.01 (m, 4 H, OCH2), 4.10 (d, J = 13.2 Hz,
1 H, CH2Ph), 4.66 (t, J = 2.1 Hz, 1 H, =CH), 4.69 (t, J = 2.6
Hz, 1 H, =CH), 7.21–7.35 (m, 5 H, ArH). 13C NMR (75
MHz, CDCl3): d = 21.4 (C-7), 21.8 (CH3), 28.6 (C-6), 42.3
(C-4), 45.5 (C-3a), 57.5 (NCH2Ar), 57.9 (C-2), 63.6 and
64.3 (OCH2), 67.8 (C-7a), 101.5 (=CH2), 102.1 (C-5), 123.7
(ArH), 128.3 (ArH), 128.4 (ArH), 139.7 (Ar), 157.4 (C-3).
(17) For the isolation of the 5-desoxo derivative, see: Mori, M.;
Saitoh, F.; Uesaka, N.; Okamura, K.; Date, T. J. Org. Chem.
1994, 59, 4993.
(1) Kobayashi, J.; Morita, H. The Alkaloids 2003, 60, 165.
(2) Morita, H.; Fujiwara, M.; Yoshida, N.; Kobayashi, J.
Tetrahedron 2000, 56, 5801.
(3) Solé, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461.
(4) Zhang, H.; Yang, S.-P.; Fan, C.-Q.; Ding, J.; Yue, J.-M.
J. Nat. Prod. 2006, 69, 533.
(5) Morita, H.; Kobayashi, J. Org. Lett. 2003, 5, 2895.
(6) (a) Saito, S.; Kubota, T.; Fukushi, E.; Kawabata, J.; Zhang,
H.; Kobayashi, J. Tetrahedron Lett. 2007, 48, 1587. (b) Li,
C.; He, H.; Wang, Y.; Mu, S.; Li, S.; Gao, Z.; Gao, Z.; Hao,
X. Tetrahedron Lett. 2007, 48, 2737; and references therein.
(7) By Zr-promoted reductive cyclization: Mori, M.; Uesaka,
N.; Saitoh, F.; Shibasaki, M. J. Org. Chem. 1994, 59, 5643.
(8) By intramolecular reaction of enol ethers with alkynes
catalyzed by Pt(II): Nevado, C.; Cárdenas, D. J.; Echavarren,
A. M. Chem. Eur. J. 2003, 9, 2627.
(9) By W(CO)5(L)-catalyzed cyclization of w-acetylenic silyl
enol ethers: Grandmarre, A.; Kusama, H.; Iwasawa, N.
Chem. Lett. 2007, 36, 66.
(10) For the synthesis of 3a-unsubstituted cis-3-methylene-
hydoindoles, see: (a) Solé, D.; Cancho, Y.; Llebaría, A.;
Moretó, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895.
(b) Lemaire-Audoire, S.; Savignac, M.; Dupuis, C.; Genêt,
J.-P. Tetrahedron Lett. 1996, 37, 2003. (c) Berteina, S.; De
Mesmaeker, A.; Wendeborn, S. Synlett 1999, 1121.
(d) Gordon, G. J.; Luker, T.; Tuckett, M. W.; Whitby, R. J.
Tetrahedron 2000, 56, 2113.
Synlett 2007, No. 15, 2379–2382 © Thieme Stuttgart · New York

2382
A. Cordero-Vargas et al.
LETTER
(18) (3RS,3aRS,7aRS)-1-Benzyl-3-hydroxymethyl-3a-
methyloctahydroindol-5-one Ethylene Acetal (4)
127.1 (ArH), 128.3 (ArH), 128.5 (ArH), 138.0 (Ar), 152,1
(C-3). IR (NaCl, neat): 3410, 3300, 2947, 2881, 2804, 1452,
1359, 1252, 1206, 1142, 1110, 1059, 1011 cm–1.
To a solution of 3 (0.9 g, 3.0 mmol) in anhyd THF (30 mL)
at r.t. was added dropwise BH3·THF complex (15 mL, 15.0
mmol; 1 M solution in THF). When the starting material was
completely consumed, the reaction was cooled to 0 °C and
3 N NaOH (6 mL) and H2O2 (3 mL of an 30% aq solution)
were carefully added to the solution. After stirring for an
hour, brine was added to the reaction and extracted with
EtOAc. The organic layers were dried, filtered, and
(20) trans-1-Benzyl-3a-methyl-3-methyleneoctahydroindol-
5-one Ethylene Acetal (10)
1H NMR (300 MHz, CDCl3, gCOSY): d = 1.18 (s, 3 H, CH3),
1.56–1.62 (m, 3 H, H-4 and H-7), 1.72–1.75 (m, 1 H, H-7),
1.91–1.96 (m, 2 H, H-6), 1.97 (dd, J = 13.2, 2.4 Hz, 1 H, H-
7), 2.04–2.12 (m, 1 H, H-7a), 2.73 (dt, J = 14.8, 2.1 Hz, 1 H,
H-2), 3.18 (d, J = 13.5 Hz, 1 H, CH2Ph), 3.70 (dt, J = 15.2,
1.9 Hz 1 H, H-2), 3.86–4.07 (m, 5 H, OCH2 and CH2Ph),
concentrated. The residue was purified by column
chromatography (SiO2, CH2Cl2–EtOAc, 98:2 to 95:5) to
afford alcohol 4 (705 mg, 76%) as a yellow oil: 1H NMR
(300 MHz, CDCl3, gCOSY): d = 1.21 (s, 3 H, CH3), 1.28 (dd,
J = 13.1, 2.2 Hz, 1 H, H-4), 1.45 (ddd, J = 12.4, 5.9, 3.2 Hz,
1 H, H-7), 1.87–1.76 (m, 2 H, H-4 and H-6), 1.91–2.11 (m,
2 H, H-6 and H-7), 2.38 (t, J = 2.6 Hz, 1 H, H-7a), 2.52 (t,
J = 10.1 Hz, 1 H, H-2), 2.74 (dd, J = 10.1, 8.2 Hz, 1 H, H-2),
3.19 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.47 (dd, J = 10.4, 8.4 Hz,
1 H, CH2OH), 3.69 (dd, J = 10.4, 5.9 Hz, 1 H, CH2OH),
3.87–3.99 (m, 4 H, OCH2), 4.02 (d, J = 13.5 Hz, 1 H,
CH2Ph), 7.20–7.32 (m, 5 H, ArH). 13C NMR (300 MHz,
CDCl3, gHSQC): d = 21.5 (C-6), 21.9 (Me), 28.6 (C-7), 36.5
(C-4), 43.0 (C-3a), 51.0 (C-3), 55.1 (C-2), 57.9 (NCH2Ar),
62.6 (CH2OH), 63.5 and 64.4 (OCH2), 68.5 (C-7a), 109.6
(C-5), 126.6 (ArH), 128.1 (ArH), 128.3 (ArH), 140.2 (Ar).
IR (NaCl, neat): 3440, 2926, 2877, 2788, 1359, 1091 cm–1.
(19) trans-1-Benzyl-3a-hydroxymethyl-3-methylene-
octahydroindol-5-one Ethylene Acetal (8)
4.58 (t, J = 2.3 Hz 1 H, =CH2), 7.22–7.37 (m, 5 H, ArH). 13
C
NMR (75 MHz, CDCl3): d = 20.3 (CH3), 21.5 (C-7), 34.6 (C-
6), 42.6 (C-4), 45.4 (C-3a), 58.1 (NCH2Ar), 58.6 (C-2), 63.6
and 63.6 (OCH2), 71.8 (C-7a), 100.0 (=CH2), 109.8 (C-5),
126.7 (ArH), 128.1 (ArH), 128.3 (ArH), 139.8 (Ar), 156.7
(C-3).
(21) For the influence of the substituent at C-3a in the reduction
of N-Boc-hexahydro-1H-indoles, see: Brodney, M. A.; Cole,
M. L.; Freemont, J. A.; Kyi, S.; Junk, P. C.; Padwa, A.;
Riches, A. G.; Ryan, J. H. Tetrahedron Lett. 2007, 48, 1939.
(22) Both precursors 2 and 6 seem to have the same preferred
conformation, according to their NMR data. For methyl
derivative 2, see ref. 15. For 6: 1H NMR (300 MHz, CDCl3):
d = 2.00 (ddd, J = 13.1, 6.5, 3.3 Hz, 1 H, H-5), 2.26 (dt,
J = 13.5, 5.2 Hz, 1 H, H-5), 2.51 (d, J = 13.0 Hz, 1 H, H-3),
2.56 (d, J = 13.7 Hz, 1 H, H-3), 2.63 (ddd, J = 15.9, 5.2, 3.0
Hz, 1 H, H-6), 3.04 (ddd, J = 15.9, 13.7, 6.5 Hz, 1 H, H-6),
3.79 (s, 3 H, OMe), 3.91–4.04 (m, 4 H, OCH2), 6.23 and 6.28
(2 s, 1 H each, =CH2), 9.47 (s, 1 H, CHO). 13C NMR (75
MHz, CDCl3): d = 33.9 (C-5), 37.6 (C-6), 39.7 (C-3), 53.0
(OMe), 61.4 (C-2), 64.3 and 64.8 (OCH2), 106.4 (C-4),
135.9 (=CH2), 147.5 (=C), 170.4 (CO2Me), 192.0 (CHO),
203.1 (C-1). IR (NaCl, neat): 2956, 2894, 1740, 1710, 1695,
1434, 1279, 12361121, 1089, 1040 cm–1.
1H NMR (300 MHz, CDCl3, NOESY): d = 1.57–1.60 (m, 2
H, H-4 and H-7), 1.74–1.89 (m, 2 H, H-4 and H-6), 1.89–
2.01 (m, 2 H, H-6 and H-7), 2.40 (dd, J = 11.9, 3.4 Hz, 1 H,
H-7a), 2.82 (td, J = 14.4, 2.4 Hz, 1 H, H-2), 3.12 (d, J = 12.9
Hz, 1 H, NCH2Ar), 3.44 (d, J = 11.0 Hz, 1 H, CH2OH), 3.69
(d, J = 14.4 Hz, 1 H, H-2), 3.86–4.00 (m, 4 H, OCH2), 4.04
(d, J = 13 Hz, 1 H, NCH2Ar), 4.40 (d, J = 11.0 Hz, 1 H,
CH2OH), 4.80 (t, J = 2.5 Hz, 1 H, =CH2), 4.88 (t, J = 2.0 Hz,
1 H, =CH2), 7.26–7.30 (m, 5 H, ArH). 13C NMR (75 MHz,
CDCl3, gHSQC): d = 21.1 (C-7), 34.5 (C-6), 40.3 (C-4), 49.5
(C-3a), 58.0 (CH2Ph), 59.9 (C-2), 63.9 and 64.7 (OCH2),
66.3 (CH2OH), 72.3 (C-7a), 103.7 (=CH2), 109.0 (C-5),
(23) (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S.
A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(b) Smith, D. M.; Woerpel, K. A. Org. Lett. 2004, 6, 2063.
(c) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem. 2006,
4, 1195.
Synlett 2007, No. 15, 2379–2382 © Thieme Stuttgart · New York

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