Intramolecular N-acyliminium ion-olefin cyclization in the synthesis of optically pure isoquinoline derivatives: Control of stereochemistry and application to synthesis of morphine alkaloids

Article abstract of DOI:10.1135/cccc19990203

The 3-[2-(cyclohex-1-enyl)ethyl]-[1,3]oxazoline-2,4-dione derivatives 9, 14 and 16 were subjected to hydride reduction followed by acid-catalyzed olefin-N-acyliminium ion cyclization to afford a series of perhydroisoquinolines 10, 11a, 11b, 19a-19c, 20a, 20b and 21. A mechanism was proposed that accounts for the observed stereoselectivity of the cyclization reactions based on the neighboring group participation by a benzoate group.

Full text of DOI:10.1135/cccc19990203

Intramolecular Cyclization
203
INTRAMOLECULAR N-ACYLIMINIUM ION-OLEFIN CYCLIZATION IN
THE SYNTHESIS OF OPTICALLY PURE ISOQUINOLINE DERIVATIVES:
CONTROL OF STEREOCHEMISTRY AND APPLICATION TO SYNTHESIS
OF MORPHINE ALKALOIDS
1
2
3,
Patricia BOTTARI , Mary Ann A. ENDOMA , Tomáš HUDLICKÝ *,
4,+
5,++
Ion GHIVIRIGA and Khalil A. ABBOUD
Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, U.S.A.;
1
2
3
e-mail: bottari@chem.ufl.edu, endoma@chem.ufl.edu, hudlicky@chem.ufl.edu,
4
5
ion@chem.ufl.edu, abboud@chem.ufl.edu
Received October 13, 1998
Accepted Decem ber 22, 1998
Dedicated to the memory of Dr Miroslav Protiva in recognition of his life-long contributions to
the chemistry of alkaloids.
Th e 3-[2-(cycloh ex-1-en yl)eth yl]-[1,3]oxazolin e-2,4-dion e derivatives 9, 14 an d 16 were sub-
jected to h ydride reduction followed by acid-catalyzed olefin -N-acylim in ium ion cyclization
to afford a series of perh ydroisoquin olin es 10, 11a, 11b, 19a–19c, 20a, 20b an d 21. A m ech -
an ism was proposed th at accoun ts for th e observed stereoselectivity of th e cyclization reac-
tion s based on th e n eigh borin g group participation by a ben zoate group.
Key w ord s: N-Acylim in ium ion ; Isoquin olin es; Stereoch em istry; Morph in e; Alkaloids;
Biooxidation .
Morph in e, th e m ajor com pon en t of opium , is a cen tral n ervous system de-
pressan t1, fin din g application s in m edicin e as poten t an algesic, h ypn otic
an d cough -suppressan t2. Curren tly, m orph in e is also bein g used as an an es-
th etic in open -h eart surgery because of its in active cardiac spectrum 3.
Alth ough th e m edicin al use of m orph in e h as been kn own for cen turies
an d som e 20 total syn th eses h ave been publish ed4, an efficien t preparation
con tin ues to be a ch allen ge to th e ch em ical com m un ity. An econ om ical
an d practical syn th esis com petitive with th e cost of extraction from opium
+ Th e auth or to wh om correspon den ce regardin g NMR sh ould be addressed.
++Th e auth or to wh om correspon den ce regardin g X-ray sh ould be addressed.
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204
Bottari et al.:
poppy an d th e n eed to syn th esize sim pler derivatives with varied biological
activity are som e of th e reason s for con tin uin g in terest. As we previously re-
ported5, isoquin olin es such as 1 an d 2 seem to be ideal in term ediates for
th e total syn th esis of eith er en an tiom er of m orph in e as th eir stereo-
ch em istry at C-10b correspon ds to th e absolute stereoch em istry at C-9 of
th e ent-m orph in e 3 an d th e n atural alkaloid 4, respectively (Sch em e 1).
Br
HO
HO
Br
5
MeO
MeO
OH
10a
OH
HO
HO
O
OH
OH
O
O
H
H
10a
9
N
N
O
NMe
NMe
10b
10b
14
H
H
1
2
O
O
3
O
HO
4
SCHEME 1
On e of our early attem pts in volved radical cyclization of a derivative of
th e vin yl brom ide 5, wh ich furn ish ed a 2 : 1 m ixture of th e isoquin olin e
derivatives 1 an d 2 in 89% com bin ed yield5, as sh own in Sch em e 1. Because
of th e low selectivity of th e radical cyclization , an oth er route was devel-
oped5 to con trol better th e access to both isoquin olin e isom ers via an
acid-catalyzed cyclization to furn ish com poun ds of th e type of 6. In con tin -
uation of our efforts in th is area6, we report h ere th e results of th e study of
2
R
3
R
6
1
7
R
5
8
9
H
10a
4
N
6
O
10b
10
3
O
2
1
th e stereocon trolled in tram olecular N-acylim in ium ion -olefin cyclization 7
to en an tiom erically pure isoquin olin e derivatives for both cis- an d trans-
series of protected diols 9a, 17 an d 18 syn th esized from th e readily avail-
able diol 7. With th is approach we were able to con trol th e stereoch em istry
at C-10a/C-10b in th e isoquin olin e in term ediates, cen ters th at correspon d
to C-14/C-9 of m orph in e, respectively. In th e cis-series (Sch em e 2), after
cyclization of th e ben zoate protected diol 9a, th e stereoch em istry at C-10b,
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Intramolecular Cyclization
205
wh ich correspon ds to C-9 of th e n atural m orph in e, was establish ed in th e
correct absolute sen se. Deh ydroch lorin ation or deh ydration reaction at
C-6a/C-10a gives th e isoquin olin e derivative 1, im portan t in term ediate in
th e n atural m orph in e syn th esis. In th e trans-series, th e adducts obtain ed
h ave on e of th e two stereocen ters C-10a or C-10b establish ed in th e correct
absolute sen se depen din g on wh eth er th e desired target is n atural or
ent-m orph in e. Th e stereoch em istry at C-10a (C-14 of n atural m orph in e) is
set in th e correct absolute sen se an d th at of C-10b (C-9 of n atural m or-
ph in e) is reversed. Epim erization at C-10b can establish th e correct
stereoch em istry of both stereocen ters C-10a/C-10b for th e n atural m or-
ph in e syn th esis. For th e ent-m orph in e approach , th e an alysis is opposite.
Th e stereocen ter C-10b is correct, an d deh ydroch lorin ation or deh ydration
reaction at C-6a/C-10a gives th e isoquin olin e derivative 2, an im portan t in -
term ediate in th e ent-m orph in e syn th esis.
Th e outcom e of th e stereoch em istry of th e isoquin olin e derivatives in th e
N-acylim in ium ion cyclization reaction of th e cis- an d trans-series in dicates
th at th e stereoch em istry at C-7 dictates th e stereoch em istry at C-10b an d
con sequen tly at th e rin g jun ction (Fig. 1). Th e steric bulkin ess of th e ben zo-
ate group at C-7 forces th e oxazolidin on e rin g to be n ear th e β-face of th e
cycloh exen e rin g. Th erefore, th e bon d form ation takes place from th e bot-
tom face of th e oxazolidin on e rin g, leadin g to a cis relation sh ip between
C-7/C-10b an d a trans between C-10a/C-10b.
EXPERIMENTAL
All n on -h ydrolytic reaction s were perform ed un der an atm osph ere of argon in solven ts dried
accordin g stan dard procedures. An alytical TLC was perform ed on silica gel 60F-254
(Wh atm an ) plates. Flash colum n ch rom atograph y was perform ed on Fish er silica gel (grade 60,
200–425 m esh ). 1H an d 13C NMR spectra were recorded on a Gem in i 300 MHz in strum en t in
CDCl3 un less oth erwise in dicated. Ch em ical sh ifts are given in ppm (δ-scale), couplin g con -
stan t (J) in Hz. All 2D NMR experim en ts were perform ed on a Varian Un ity 500 MHz in stru-
O
O
N
H
10b
H
10a
H
H
7
BzO
BzO
FIG. 1
Align m en t for cyclization
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Bottari et al.:
m en t. Mass spectra were recorded on a Fin n igan Mat 95 Q m ass spectrom eter. IR spectra
(waven um bers in cm –1) were obtain ed on a Perkin –Elm er 1600 Series in strum en t. X-Ray
crystallograph y data obtain ed on a Siem en s SMART Platform equipped with a CCD area de-
tector. Optical rotation s were m easured on a Perkin –Elm er polarim eter an d [α]D values are
given in 10–1 deg cm 2 g–1. Elem en tal an alyses were perform ed by Atlan tic Microlabs, In c.
Meltin g poin ts were m easured on a Un im elt apparatus.
(5S,6S)-5,6-Di(ben zoyloxy)-1-(2-brom oeth yl)cycloh ex-1-en e (8)
To a stirred solution of diol8 12 (2.0 g, 9.1 m m ol), ben zoic acid (2.8 g, 22.8 m m ol), an d cat-
alytic am oun ts of DMAP in CH2Cl2 (80 m l) at 0 °C was added a solution of DCC (4.68 g,
22.8 m m ol) in CH2Cl2 (10 m l). Th e reaction was allowed to warm up to room tem perature
overn igh t, an d th e solid was filtered th rough celite. Th e solven ts were evaporated un der re-
duced pressure an d th e residue was purified by flash ch rom atograph y on silica gel (1 : 11
eth yl acetate–h exan es) to afford th e title com poun d as a yellow oil in 83% yield, [α]2D6 –106.7
(MeOH, c 0.39). 1H NMR (CDCl3): 2.00–2.70 (6 H, m ); 3.49 (2 H, t, J = 7.1); 5.38 (1 H, dt, J =
11.2 an d 3.7); 5.91 (1 H, d, J = 3.4); 5.94 (1 H, t, J = 3.9); 7.30–7.58 (6 H, m ); 7.85 (2 H, d,
J = 8.0); 8.05 (2 H, d, J = 8.0). 13C NMR (CDCl3): 22.7, 24.1, 31.0, 37.4, 68.2, 71.0, 128.2,
128.4, 129.6, 129.7, 129.9, 130.0, 130.9, 131.3, 132.8, 133.1, 165.7, 166.3. IR (n eat): 2 932,
1 721, 1 601, 1 277, 1 114, 710. HRMS (CI), m/z for C22H22BrO4 calculated: 429.0701; foun d:
429.0741.
3-{2-[(5S,6S)-5,6-Di(ben zoyloxy)cycloh ex-1-en yl]eth yl}-[1,3]oxazolidin e-2,4-dion e (9)
To a stirred solution of com poun d 8 (3.1 g, 7.2 m m ol) in dry THF (60 m l) was added
oxazolidin edion e (0.88 g, 8.7 m m ol) followed by 1,1,3,3-tetram eth ylguan idin e (1.1 m l,
8.7 m m ol). Th e cloudy solution was h eated at reflux for 48 h an d th en filtered th rough
celite. Th e solven ts were evaporated un der reduced pressure, an d th e residue was purified by
flash ch rom atograph y on silica gel (h exan es) to furn ish th e title com poun d in 77% yield,
m .p. 54–54.5 °C, [α]3D0 –124.9 (MeOH, c 0.43). 1H NMR (CDCl3): 1.2–1.4 (2 H, m ); 2.00–2.50
(6 H, m ); 3.74 (2 H, m ); 4.66 (2 H, s); 5.37 (1 H, dt, J = 3.7 an d 10.7); 5.82 (1 H, s); 6.00
(1 H, s); 7.29 (2 H, m ); 7.45 (3 H, m ); 7.57 (1 H, m ); 7.85 (2 H, d, J = 7.1); 8.06 (2 H, d, J =
7.1). 13C NMR (CDCl3): 22.8, 24.0, 31.9, 38.5, 67.8, 68.0, 70.8, 128.2, 128.4, 129.8, 129.9,
130.1, 130.6, 130.8, 132.8, 133.1, 155.7, 165.6, 166.4, 170.3. IR (n eat): 2 929, 1 815, 1 743,
1 450, 1 277. LRMS (CI), m/z (%): 396 (20), 264 (20), 206 (25), 178 (100). For C25H23NO7
calculated: 66.82% C, 5.12% H, 3.12% N; foun d: 66.63% C, 5.51% H, 3.02% N.
(6aR,7R,8S,10aR,10bS)-7,8-Di(ben zoyloxy)-6a-h ydroxy-1,5,6,6a,7,8,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (10)
To a solution of com poun d 9 (0.80 g, 1.78 m m ol) in MeOH (20 m l) at 0 °C was added
NaBH4 (0.68 g, 17.8 m m ol) in on e portion . Th e reaction was stirred for 30 m in an d
quen ch ed with aceton e. Th e solven ts were evaporated un der reduced pressure an d th e resi-
due extracted with eth er (20 m l). Th e eth er solution was th en wash ed with brin e (2 × 10 m l)
an d th e solven ts were evaporated un der reduced pressure to afford com poun d 9a (0.67 g) in
80% crude yield. Com poun d 9a was used as crude m aterial in th e n ext step.
To a solution of 9a (0.67 g, 1.48 m m ol) in dry CH2Cl2 (20 m l) un der argon at 0 °C was
added BF3·Et2O (1.92 m l, 14.8 m m ol) dropwise. Th e reaction m ixture was stirred at 0 °C for
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Intramolecular Cyclization
207
1 h , an d th en allowed to warm up to room tem perature overn igh t. Th e reaction was
quen ch ed with saturated NaHCO3 solution (10 m l), wash ed with brin e, an d dried over an -
h ydrous Na2SO4. Th e organ ic solven ts were evaporated un der reduced pressure an d th e resi-
due was purified by flash ch rom atograph y on silica gel (1 : 1 h exan es–eth yl acetate) to
afford th e title com poun d in 55% yield, m .p. 87.5–88 °C, [α]2D6 +110.4 (MeOH, c 1.0).
1H NMR (500 MHz, CDCl3): 1.39 (1 H, d, J = 14.9); 1.51 (1 H, td, J = 5.5 an d 13.6); 1.91
(1 H, d, J = 15.0); 1.92 (1 H, t, J = 15.4); 1.95 (1 H, d, J = 12.8); 2.11 (1 H, dq, J = 2.9 an d
15.6); 2.43 (1 H, tt, J = 4.5 an d 14.9); 3.07 (1 H, td, J = 2.9 an d 13.7); 3.60 (OH, s); 3.84 (1 H,
ddd, J = 1.5, 5.7 an d 14.3); 3.91 (1 H, ddd, J = 5.3, 8.1 an d 12.3); 4.01 (1 H, dd, J = 5.2 an d
8.7); 4.45 (1 H, t, J = 8.4); 5.52 (1 H, d, J = 3.6); 5.77 (1 H, q, J = 3.0); 7.35 (2 H, t, J = 7.5);
7.47 (2 H, t, J = 7.5); 7.53 (1 H, t, J = 7.3); 7.60 (1 H, t, J = 7.9); 7.93 (2 H, d, J = 7.9); 8.01
(2 H, d, J = 7.9). 13C NMR (125 MHz, CDCl3): 15.9, 24.2, 32.9, 37.7, 46.7, 52.9, 66.7, 67.9,
70.7, 72.2, 128.3, 128.9, 129.3, 133.5, 133.9, 156.7, 165.2, 165.8. IR (CHCl3): 3 467, 2 954,
1 720, 1 276, 1 115. HRMS (EI), m/z for C25H25NO7 calculated: 451.1631; foun d: 451.1582.
For C25H25NO7 calculated: 66.52% C, 5.54% H, 3.10% N; foun d: 66.56% C, 5.79% H,
3.07% N.
(6aR,7S,8S,10aR,10bS)-7,8-Di(ben zoyloxy)-6a-ch loro-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (11a) an d
(6aS,7S,8S,10aR,10bS)-7,8-Di(ben zoyloxy)-6a-ch loro-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (11b)
To a solution of 9a (2.6 g, 5.8 m m ol) in dry CH2Cl2 (90 m l) un der argon at 0 °C was added
AlCl3 (7.70 g, 57.6 m m ol) in on e portion . Th e reaction m ixture was allowed to warm up to
room tem perature an d stirred overn igh t. Th e excess of AlCl3 was carefully quen ch ed with
water (50 m l). Th e organ ic layer was separated an d th e water layer extracted with CH2Cl2
(2 × 25 m l). Th e com bin ed organ ic extracts were wash ed with brin e an d dried over an h y-
drous Na2SO4. Th e organ ic solven ts were evaporated un der reduced pressure an d th e residue
was purified by flash ch rom atograph y on silica gel (1 : 1 eth yl acetate–h exan es) to afford
57% yield of th e isom ers 11a an d 11b with a 3.7 : 1 ratio, respectively (HPLC ratio, 65 : 35
H2O–MeCN).
Compound 11a: m .p. 230–231 °C (dec.), [α]3D1 +93.9 (CHCl3, c 1.22). 1H NMR (500 MHz,
CDCl3): 1.47 (1 H, dq, J = 2.8 an d 15.0); 1.97 (1 H, m ); 2.00 (1 H, m ); 2.10 (1 H, dq, J = 2.9
an d 15.7); 2.29 (1 H, dt, J = 2.0 an d 14.5); 2.30 (1 H, m ); 2.66 (1 H, tt, J = 4.3 an d 14.9); 3.16
(1 H, ddd, J = 2.7, 13.0 an d 14.1); 3.82 (1 H, ddd, J = 1.6, 5.6 an d 14.3); 4.02 (1 H, m ); 4.05
(1 H, m ); 4.49 (1 H, m ); 5.69 (1 H, d, J = 4.0); 5.74 (1 H, q, J = 3.3); 7.37 (2 H, t, J = 7.8);
7.46 (2 H, t, J = 7.6); 7.54 (1 H, t, J = 7.5); 7.59 (1 H, t, J = 7.5); 7.96 (2 H, d, J = 8.3); 8.14
(2 H, d, J = 8.3). 13C NMR (CDCl3): 17.11, 24.35, 37.10, 38.20, 48.48, 52.92, 66.64, 67.30,
68.12, 69.29, 128.39, 128.45, 128.60, 129.69, 133.14, 133.62, 156.49, 165.46, 165.77. IR
(KBr): 2 931, 1 761, 1 720, 1 450, 1 420, 1 268, 1 103, 1 068, 710. HRMS (FAB), m/z for
C25H25ClNO6 calculated (M+) 470.1370; foun d: 470.1362. For C25H24ClNO6 calculated:
63.90% C, 5.15% H, 2.98% N; foun d: 63.80% C, 5.17% H; 3.01% N.
Compound 11b: m .p. 223–225 °C (dec.), [α]3D1 +12.8 (CHCl3, c 0.72). 1H NMR (500 MHz,
CDCl3): 1.68 (1 H, dt, J = 4.4 an d 12.0); 1.74 (1 H, dddd, J = 3.4, 12.0, 12.0 an d 12.0); 1.89
(1 H, dd, J = 3.3 an d 13.7); 1.95 (1 H, td, J = 4.2 an d 10.9); 1.96 (1 H, dddd, J = 4.5, 12.1,
12.1 and 12.9); 2.02 (1 H, ddd, J = 6.0, 13.2 and 13.8); 2.20 (1 H, dddd, J = 4.2, 4.5, 4.5 and 12.9);
3.43 (1 H, ddd, J = 3.3, 12.3 an d 13.7); 3.81 (1 H, ddd, J = 5.6, 8.1 an d 9.9); 3.88 (1 H, d, J =
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Bottari et al.:
5.2 an d 13.7); 4.12 (1 H, dd, J = 5.5 an d 8.8); 4.45 (1 H, t, J = 8.6); 5.77 (1 H, d, J = 2.5); 5.85
(1 H, ddd, J = 3.2, 4.5 an d 12.1); 7.28 (2 H, t, J = 7.7); 7.47 (1 H, t, J = 7.5); 7.51 (2 H, t, J =
7.7); 7.65 (1 H, t, J = 7.4); 7.79 (2 H, d, J = 7.9); 8.03 (2 H, d, J = 7.6). 13C NMR (CDCl3):
21.53, 25.31, 34.54, 36.60, 43.14, 54.05, 65.59, 69.49, 72.52, 73.71, 128.30, 128.81, 129.04,
129.60, 129.75, 133.08, 133.84, 156.48, 165.20, 165.40. IR (CHCl3): 2 936, 1 751, 1 728,
1 452, 1 277. LRMS (CI), m/z (%): 470 (M+, 40), 312 (35), 190 (25), 105 (100).
(1R,6S)-2-(2-Brom oeth yl)-6-(tert-butyldim eth ylsilyloxy)cycloh ex-2-en -1-ol (12a)
To a stirred solution of th e diol8 12 (1.63 g, 7.39 m m ol) in dry CH2Cl2 (50 m l) un der argon
at –78 °C, was added N,N-diisopropyleth ylam in e (2.70 m l, 15.5 m m ol), resultin g in a wh ite
suspen sion . After 10 m in , tert-butyl(dim eth yl)silyl triflate (1.87 m l, 8.13 m m ol) was added
dropwise, an d stirrin g/coolin g con tin ued. After 5 h , excess of tert-butyl(dim eth yl)silyl triflate
(0.85 m l, 3.7 m m ol) was added dropwise, an d th e stirred m ixture was allowed to warm up to
room tem perature overn igh t. After 20 h , th e reaction was quen ch ed with water (80 m l) an d
saturated aqueous NH4Cl (30 m l), an d extracted with CH2Cl2 (4 × 80 m l). Th e com bin ed or-
gan ic fraction s were dried over MgSO4, filtered an d th e solven ts were evaporated un der re-
duced pressure to yield a brown oil. Purification by flash ch rom atograph y on silica gel
(50 : 1 h exan es–eth yl acetate), afforded th e title com poun d as a colorless oil in 70% yield,
[α ]2D5 –42.0 (CHCl3, c 1.0). 1H NMR (400 MHz, CDCl3): 0.11 (6 H, s); 0.92 (9 H, s); 1.57 (1 H,
m ); 1.78 (1 H, m ); 2.03 (1 H, m ); 2.18 (1 H, m ); 2.63 (2 H, m ); 2.76 (1 H, m ); 3.53 (2 H, m );
3.81 (1 H, dt, J = 10.6 an d 3.7); 3.9 (1 H, t, J = 3.5); 5.65 (1 H, m ). 13C NMR (100 MHz,
CDCl3): –4.9, –4.5, 18.0, 23.9, 25.4, 25.7, 31.8, 38.4, 68.6, 70.7, 127.7, 134.7. IR (KBr): 3 560,
2 970, 2 930, 1 260, 1 100. HRMS (CI), m/z for C14H27BrO2Si calculated: 335.3550; foun d:
335.3550.
(3S,4S)-3-Ben zoyloxy-2-(2-brom oeth yl)-4-(tert-butyldim eth ylsilyloxy)cycloh ex-1-en e (13)
To a stirred solution of th e alcoh ol 12a (4.61 g, 13.7 m m ol) an d ben zoic acid (1.85 g,
15.1 m m ol) in dry THF (12 m l) at 0 °C was added a solution of th e Mitsun obu reagen t,
wh ich was previously prepared by addition of DEAD (4.79 g, 27.5 m m ol) to a stirred solu-
tion of Bu3P (5.56 g, 27.5 m m ol) in dry THF (12 m l) at 0 °C, an d stirred at th e sam e tem per-
ature for 20 m in . Th e reaction m ixture was th en allowed to warm up to room tem perature.
After 16 h , th e solven ts were evaporated un der reduced pressure to furn ish yellow oil, wh ich
was pre-purified by passage th rough a silica plug with ben zen e. Purification by flash ch ro-
m atograph y on silica gel (ben zen e) afforded th e title com poun d in 84.7% yield, m .p.
65–66 °C, [α ]2D5 +102.0 (CH3, c 1.0). 1H NMR (400 MHz, CDCl3): 0.3 (3 H, s); 0.5 (3 H, s); 0.84
(9 H, s); 1.74 (1 H, m ); 1.82 (1 H, m ); 2.11 (1 H, m ); 2.30 (1 H, m ); 2.50 (1 H, m ); 2.60 (1 H, m );
3.45 (2 H, m ); 4.02 (1 H, ddd, J = 2.9, 4.73 an d 7.02); 5.40 (1 H, d, J = 4.42); 5.84 (1 H, bt, J
= 3.6); 7.45 (2 H, tm , J = 7.6); 7.57 (1 H, ddt, J = 1.38, 6.87 an d 7.93); 8.05 (2 H, dm , J =
8.5). 13C NMR (100 MHz, CDCl3): –4.88, –4.86, 17.8, 22.1, 25.6, 27.2, 31.1, 37.5, 69.2, 73.4,
128.4, 129.7, 130.1, 130.3, 130.8, 133.0, 166.1. IR (KBr): 2 928, 2 858, 1 714, 1 258, 1 114,
836. HRMS (CI), m/z for C21H32O3BrSi calculated: 439.1304; foun d: 439.1291.
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Intramolecular Cyclization
209
3-{2-[(5S,6S)-6-Ben zoyloxy-5-(tert-butyldim eth ylsilyloxy)cycloh ex-1-en yl]eth yl}-
[1,3]oxazolidin e-2,4-dion e (14)
To a stirred solution of com poun d 13 (0.23 g, 0.52 m m ol) in dry THF (5 m l) was added
oxazolidin e-2,4-dion e (0.114 g, 1.05 m m ol), followed by 1,1,3,3-tetram eth ylguan idin e
(0.13 m l, 1.05 m m ol). Th e cloudy solution was refluxed for 48 h , an d th en filtered th rough
celite. Th e solven ts were evaporated un der reduced pressure, an d th e residue was purified by
flash ch rom atograph y on silica gel (h exan es) to furn ish th e title com poun d in 85% yield,
m .p. 68–69 °C, [α ]2D6 +80 (CH2Cl2, c 0.59). 1H NMR (CDCl3): –0.07 (3 H, s); –0.01 (3 H, s);
0.74 (9 H, s); 1.67–1.79 (2 H, m ); 2.08–2.29 (4 H, m ); 3.51–3.70 (2 H, m ); 3.94 (1 H, m ); 4.56
(2 H, s); 5.51 (1 H, d, J = 5.1); 5.66 (1 H, s); 7.38 (1 H, dd, J = 8.3); 7.47 (1 H, d, J = 7.6); 8.02
(1 H, d, J = 8.3). 13C NMR (CDCl3): –5.0, –4.9, 17.8, 22.7, 25.5, 28.0, 31.1, 38.9, 67.6, 69.9,
74.6, 128.1, 128.2, 129.4, 129.6, 130.1, 130.7, 132.9, 155.6, 166.0, 170.1. IR (CDCl3): 2 953,
2 856, 1 817, 1 746, 1 602, 1 264. HRMS (CI), m/z for C24H34NSiO6 calculated: 460.2155;
foun d: 460.2144. For C24H34NSiO6 calculated: 62.75% C, 7.19% H, 3.05% N; foun d:
62.96% C, 7.00% H, 3.04% N.
3-(2-(5S,6S)-6-Ben zoyloxy-5-h ydroxy-1-cycloh exen eyl)eth yl[1,3]oxazolidin e
-2,4-dion e (15)
To a stirred solution of th e 14 (1.1 g, 2.4 m m ol) in MeOH (70 m l) was added con cen trated
HCl (1.5 m l). After 30 m in , th e solven ts were evaporated un der reduced pressure an d th e
residue purified by flash ch rom atograph y on silica gel (3 : 1 h exan es–eth yl acetate) to afford
a quan titative yield of th e title com poun d, [α ]2D5 +91.7 (EtOAc, c 2.3). 1H NMR (CDCl3):
1.78–2.35 (6 H, m ); 2.95 (1 H); 3.73 (1 H, m ); 3.95 (1 H, m ); 3.98 (1 H, m ); 4.62 (2 H, s); 5.58
(1 H, d, J = 5.1); 5.72 (1 H, s); 7.42 (2 H, t, J = 7.5); 7.55 (1 H, t, J = 8.5); 8.02 (2 H, d, J =
6.9). 13C NMR (CDCl3): 22.3, 26.7, 31.3, 38.4, 67.8, 69.4, 73.9, 128.3, 129.6, 129.7, 130.0,
130.5, 133.2, 155.8, 166.8, 170.6. IR (n eat): 3 501, 2 932, 1 815, 1 730, 1 452, 1 271. HRMS
(CI), m/z for C18H20NO6 calculated: 346.1290; foun d: 346.1295.
3-(2-(5S,6S)-5,6-Diben zoyloxy-1-cycloh exen yl)eth yl[1,3]oxazolidin e-2,4-dion e (16)
To
a stirred solution of th e alcoh ol 15 (0.70 g, 2.02 m m ol), ben zoic acid (0.50 g,
4.04 m m ol), an d catalytic am oun t of DMAP in dry CH2Cl2 (30 m l) at 0 °C was added a solu-
tion of DCC (0.83 g, 4.04 m m ol) in dry CHCl2 (3 m l). Th e reaction was allowed to warm up
to room tem perature overn igh t, an d th e solid was filtered th rough celite. Th e solven ts were
evaporated un der reduced pressure an d th e residue was purified by flash colum n ch rom atog-
raph y on silica gel (1 : 1 eth yl acetate–h exan es) to afford th e title com poun d as a yellow oil
in 77% yield, m .p. 51.5–52 °C, [α ]D26 +125.3 (CH2Cl2, c 2.16). 1H NMR (CDCl3): 1.95–2.41
(6 H, m ); 3.67 (1 H, m ); 3.80 (1 H, m ); 4.63 (2 H, s); 5.38 (1 H, m ); 5.80 (1 H, s); 6.05 (1 H, d ,
J = 5.2); 7.42 (6 H, m ); 7.99 (4 H, m ). 13C NMR (CDCl3): 23.1, 25.1, 31.0, 38.8, 67.8, 71.4,
72.8, 128.4, 128.5, 129.6, 129.7, 129.8, 129.9, 130.0, 131.2, 133.3, 155.8, 165.9. IR (CHCl3):
1 743, 1 721, 1 450, 1 276, 1 108. HRMS (FAB), m/z for C25H24NO7 calculated: 450.1553;
foun d: 450.1558. For C25H24NO7 calculated: 66.82% C, 5.12% H, 3.12% N; foun d: 67.09% C,
5.46% H, 3.06% N.
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Bottari et al.:
(6aS,7R,8S,10aS,10bR)-6a-Ben zoyloxy-7,8-dih ydroxy-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (19a),
(6aS,7R,8S,10aS,10bR)-7-Ben zoyloxy-6a,8-dih ydroxy-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (19b) an d
(6aS,7S,8S,10aS,10bR)-7-Ben zoyloxy-8-(1-tert-butyldim eth ylsilyloxy)-6a-h ydroxy-
1,5,6,6a,7,8,9,10,10a,10b-decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (19c)
To a solution of com poun d 14 (0.17 g, 0.36 m m ol) in MeOH (5 m l) at 0 °C was added
NaBH4 (0.14 g, 3.6 m m ol) in on e portion . Th e reaction was stirred for 30 m in an d quen ch ed
with aceton e. Th e solven ts were evaporated un der reduced pressure an d th e residue ex-
tracted with eth er (10 m l). Th e eth er solution was th en wash ed with brin e (2 × 5 m l) an d
th e solven ts were evaporated un der reduced pressure to afford com poun d 17 (0.14 g) in 82%
crude yield. Com poun d 17 was used as crude m aterial in th e n ext step.
To a solution of 17 (0.14 g, 0.30 m m ol) in dry CH2Cl2 (5 m l) un der argon at 0 °C was
added BF3·Et2O (0.39 m l, 3.0 m m ol) dropwise. Th e reaction m ixture was stirred at 0 °C for
1 h , an d th en allowed to warm up to room tem perature overn igh t. Th e reaction was
quen ch ed with saturated NaHCO3 solution (5 m l), wash ed with brin e an d dried over an h ydrous
Na2SO4. Th e solven ts were evaporated un der reduced pressure an d th e TLC an alysis showed a
complex mixture of products. Flash chromatography on silica gel (1 : 1 ethyl acetate–hexanes) led
to th e separation of eigh t products in
a total of 55 m g. Th e th ree m ajor products
(19a : 19b : 19c, ratio of 7.3 : 3.3 : 1), m akin g 84% of th e total isolated m ass, were iden ti-
fied.
Compound 19a: m .p. 196–197 °C, [α ]D31 +1.44 (CHCl3). 1H NMR (CDCl3): 1.5 (2 H, m ); 1.9
(1 H, dt, J = 5.22 an d 12.92); 2.05 (2 H, m ); 2.4 (1 H, dd, J = 4.4 an d 10.4); 2.89 (1 H, d, J =
12.91); 3.2 (1 H, dt, J = 2.75 an d 13.73); 3.8 (2 H, m ); 4.0 (3 H, m ); 4.46 (1 H, t, J = 7.69);
7.48 (2 H, t, J = 7.69); 7.63 (1 H, t, J = 7.42); 7.98 (2 H, d, J = 7.42). 13C NMR (CDCl3): 19.62,
27.63, 29.01, 37.98, 44.64, 53.64, 66.45, 70.58, 72.71, 88.15, 128.65, 129.51, 129.89, 133.94,
156.75, 167.0. IR (KBr): 3 383, 3 050, 1 752, 1 267. LRMS (FAB), m/z (%): 348 (M+, 5); 226
(100), 154 (30), 137 (25), 136 (25), 123 (20), 105 (25).
Compound 19b: 1H NMR (CDCl3): 1.5 (4 H, m ); 1.8 (1 H, d, J = 4.12 Hz); 1.98 (1 H, bs);
2.08 (1 H, bs); 2.22 (1 H, dt, J = 4.69 an d 14.54); 3.24 (1 H, dt, J = 3.3 an d 13.46); 3.84 (1 H, dd,
J = 4.12 an d 15.38); 4.26 (1 H, m ); 4.44 (1 H, t, J = 7.69); 5.36 (1 H, d, J = 9.34); 7.5 (2 H, t, J =
7.42); 7.6 (1 H, t, J = 7.42); 8.1 (2 H, d, J = 7.14). 13C NMR (CDCl3): 19.30, 28.60, 29.68,
38.01, 45.93, 52.86, 66.48, 69.73, 73.71, 75.76, 128.68, 129.50, 129.89, 133.79, 156.6, 167.0.
LRMS (FAB), m/z (%): 348 (M+, 25), 219 (20), 155 (25), 154 (100), 149 (25), 137 (75), 136 (85),
107 (30), 105 (50).
Compound 19c: 1H NMR (CDCl3): –0.2 (3 H, s); 0.0 (3 H, s); 0.68 (9 H, s); 1.6 (6 H, m ); 1.9
(1 H, m ); 2.15 (1 H, t, J = 14.28); 3.23 (1 H, dt, J = 3.02 an d 13.73); 3.8 (1 H, dd, J = 3.84 an d
14.29); 4.0 (2 H, m ); 4.2 (1 H, m ); 4.4 (1 H, t, J = 7.69); 5.38 (1 H, d, J = 9.06); 7.46 (2 H, t,
J = 7.42); 7.58 (1 H, t, J = 7.42); 8.04 (2 H, d, J = 7.14). 13C NMR (CDCl3): –4.95, –4.38,
17.65, 19.22, 25.45, 29.59, 34.25, 38.06, 45.74, 52.81, 66.42, 70.16, 73.84, 75.19, 128.51,
129.50, 129.81, 133.45, 156.6, 167.0. LRMS (FAB), m/z (%): 462 (M+, 20), 322 (20), 179 (50),
137 (15), 136 (15), 105 (100).
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Intramolecular Cyclization
211
(6aS,7R,8S,10aS,10bR)-7,8-Di(ben zoyloxy)-6a-h ydroxy-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (20a) an d
(6aS,7R,8S,10aS,10bR)-6a,8-Di(ben zoyloxy)-7-h ydroxy-1,5,6,6a,7,8,9,10,10a,10b-
h ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (20b)
To a solution of com poun d 16 (0.29 g, 0.66 m m ol) in MeOH (5 m l) at 0 °C was added
NaBH4 (0.25 g, 6.6 m m ol) in on e portion . Th e reaction was stirred for 30 m in an d quen ch ed
with aceton e. Th e solven ts were evaporated un der reduced pressure an d th e residue ex-
tracted with eth er (10 m l). Th e eth er solution was th en wash ed with brin e (2 × 5 m l) an d
th e solven ts were evaporated un der reduced pressure to afford com poun d 18 (0.24 g) in 83%
crude yield. Com poun d 18 was used as crude m aterial in th e n ext step.
To a solution of th e crude 18 (0.24 g, 0.53 m m ol) in dry CH2Cl2 (10 m l) un der argon at
0 °C was added BF3·Et2O (0.68 m l, 5.3 m m ol) dropwise. Th e reaction m ixture was stirred at
0 °C for 1 h , an d th en allowed to warm up to room tem perature overn igh t. Th e reaction was
quen ch ed with saturated NaHCO3 solution (5 m l), wash ed with brin e, an d dried over an h y-
drous Na2SO4. Th e organ ic solven ts were evaporated un der reduced pressure an d th e residual
m ixture of products was purified by flash ch rom atograph y on silica gel (1 : 1 eth yl ace-
tate–h exan es). Four products in a total of 174 m g were isolated. Th e two m ajor products
(20a : 20b, ratio of 1.4 : 1), wh ich represen t 70% of th e total isolated m ass, were iden tified.
Compound 20a : m .p. 195.5–196 °C, [α ]3D0 +60.2 (CHCl3, c 0.97). 1H NMR (500 MHz,
CDCl3): 1.41 (1 H, ddd, J = 3.0, 5.0 an d 14.9); 1.51 (1 H, td, J = 5.5 an d 13.3); 1.63 (1 H,
dddd, J = 5.5, 10.0, 14.4 an d 14.7); 1.75 (1 H, ddd, J = 1.6, 3.1 an d 13.5); 1.80 (1 H, dd, J =
4.6 an d 11.3); 2.20 (1 H, ddt, J = 1.6, 4.7 an d 14.4); 2.31 (1 H, tt, J = 4.7 an d 14.5); ≈2.70
(OH, bs); 3.21 (1 H, td, J = 3.1 an d 13.7); 3.80 (1 H, ddd, J = 1.6, 5.5 an d 14.3); 3.94 (1 H,
dd, J = 5.1 an d 8.4); 3.98 (1 H, ddd, J = 5.0, 7.8 an d 12.0); 4.39 (1 H, t, J = 8.1); 5.64 (1 H, td,
J = 4.8 an d 9.9); 5.67 (1 H, d, J = 10.2); 7.21 (2 H, t, J = 7.6); 7.24 (2 H, t, J = 7.8); 7.38 (2 H, t,
J = 7.7); 7.78 (2 H, d, J = 8.3); 7.88 (2 H, d, J = 8.3). 13C NMR (CDCl3): 19.09, 25.64, 33.79,
38.0, 45.67, 52.81, 66.51, 72.20, 72.48, 73.46, 128.28, 128.42, 128.69, 129.46, 129.72,
133.05, 133.49, 156.81, 165.98, 166.08. IR (KBr): 3 511, 3 434, 1 748, 1 732, 1 698, 1 278,
1 112. LRMS (EI), m/z (%): 452 (M+, 5), 407 (10), 346 (15), 310 (13), 286 (70), 208 (40), 105
(100).
Compound 20b: m .p. 141–142 °C, [α ]D30 +42.6 (CHCl3, c 0.97). 1H NMR (500 MHz, CDCl3):
1.54 (1 H, ddd, J = 3.0, 5.6 an d 14.4); 1.75 (1 H, dddd, J = 5.6, 11.1, 14.1 an d 14.2); 2.10
(1 H, tt, J = 4.7 an d 14.4); 2.16 (1 H, dddd, J = 3.0, 4.7, 4.9 an d 14.1); 2.28 (1 H, td, J = 5.9
an d 13.0); 2.75 (1 H, ddd, J = 1.5, 3.3 an d 13.0); 2.81 (1 H, dd, J = 4.6 an d 10.8); 3.16 (1 H,
ddd, J = 3.3, 13.3 an d 14.2); 3.81 (1 H, s); 4.00 (1 H, ddd, J = 1.6, 5.7 an d 14.0 Hz); 4.02
(1 H, m ); 4.02 (1 H, m ); 4.04 (1 H, m ); 4.17 (1 H, d, J = 10.2); 4.46 (1 H, m ); 5.43 (1 H, ddd, J =
1.9, 10.2 an d 11.); 7.45 (2 H, t, J = 7.9); 7.49 (2 H, t, J = 7.9); 7.58 (1 H, t, J = 7.6); 7.62 (1 H, t,
J = 7.4); 8.03 (2 H, d, J = 7.9); 8.08 (2 H, d, J = 7.9). 13C NMR (CDCl3): 19.68, 25.75, 27.98,
38.03, 42.67, 53.48, 66.53, 70.72, 73.71, 87.87, 128.42, 128.69, 129.71, 129.84, 133.24,
133.76, 156.65, 166.02, 166.80. IR (KBr): 3 414, 2 932, 1 749, 1 708, 1 450, 1 314, 1 273,
1 109. HRMS (FAB), m/z for C25H25NO7 calculated: 452.1709; foun d: 452.1691.
(6aS,7R,8S,10aS,10bR)-7,8-Di(ben zoyloxy)-6a-ch loro-1,5,6,6a,7,8,9,10,10a,10b-
decah ydro[1,3]oxazolo[4,3-a]isoquin olin -3(3H)-on e (21)
To a solution of th e crude 18 (0.21 g, 0.47 m m ol) in dry CH2Cl2 (5 m l) un der argon at 0 °C
was added AlCl3 (0.63 m g, 4.7 m m ol) in on e portion . Th e reaction m ixture was stirred an d
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

212
Bottari et al.:
allowed to warm up to room tem perature overn igh t. Th e excess of AlCl3 was carefully
quen ch ed with water (3 m l). Th e organ ic layer was separated an d th e water layer extracted
with CH2Cl2 (2 × 5 m l). Th e com bin ed organ ic extracts were wash ed with brin e an d dried
over an h ydrous Na2SO4. Th e organ ic solven ts were con cen trated un der reduced pressure an d
th e crude m aterial was purified by flash ch rom atograph y on silica gel (7 : 3 eth yl
acetate–hexanes) to afford 70% yield of the title com pound as a single isom er: m .p. 215–217 °C,
[α ]3D0 +81.8 (CHCl3, c 1.01). 1H NMR (500 MHz, CDCl3): 1.59 (1 H, d, J = 14.9); 1.72 (1 H, qd,
J = 5.2 and 13.1); 2.03 (1 H, td, J = 5.4 and 13.5); 2.19 (1 H, dd, J = 4.3 and 11.2); 2.22 (1 H, d, J =
13.9); 2.37 (1 H, m ); 2.50 (1 H, tt, J = 4.7 an d 14.9); 3.34 (1 H, td, J = 3.3 an d 13.6); 3.84
(1 H, dd, J = 5.1 an d 13.9); 4.02 (1 H, dd, J = 4.9 an d 9.0); 4.14 (1 H, ddd, J = 5.2, 8.1 an d
11.6); 4.47 (1 H, t, J = 8.4); 5.67 (1 H, td, J = 5.5 an d 10.5); 5.90 (1 H, d, J = 9.7); 7.32 (2 H, t,
J = 7.6); 7.38 (2 H, t, J = 7.6); 7.46 (1 H, t, J = 7.6); 7.51 (1 H, t, J = 7.6); 7.86 (2 H, d, J = 7.6);
8.01 (2 H, d, J = 7.6). 13C NMR (CDCl3): 20.07, 25.58, 36.28, 38.10, 48.18, 53.13, 66.39,
70.20, 72.64, 72.99, 128.27, 128.45, 128.72, 129.43, 129.87, 133.08, 133.62, 156.48, 165.58,
166.04. IR (KBr): 3 058, 2 944, 1 763, 1 722, 1 447, 1 318, 1 271, 708. LRMS (CI), m/z (%):
470 (M+, 40); 390 (35), 308 (25), 190 (25), 105 (100). For C25H24ClNO6 calculated: 63.90% C,
5.15% H, 2.98% N; foun d: 63.88% C, 5.20% H, 3.01% N.
RESULTS AND DISCUSSION
Biooxidation of (2-brom oeth yl)ben zen e with E. coli JM109 (DTG601, ref.9)
gave a rem arkably h igh yield of th e dien ediol8 7 (8 g/l), wh ich was ch osen
as th e startin g m aterial for th e preparation of both series of ben zoate-
protected diols (Sch em e 2). Th e reduction of th e less substituted double
O
Br
Br
N
O
HO
HO
BzO
BzO
BzO
BzO
(i)
(iii)
X
(ii)
9, X = O
9a, X = OH, H
(iv)
7
8
BzO
1
BzO
1
R
R
BzO
BzO
(v)
H
N
10b
H
N
10b
+
10a
10a
O
O
H
H
O
O
1
1
10, R = OH
1
11b, R = Cl
11a, R = Cl
(i) PAD/AcOH/MeOH, 80% yield; (ii) PhCOOH/DCC/DMAP/CH Cl , 83% yield;
2
(iii) oxazolidione/1,1,3,3-tetramethylguanidin/THF/reflux, 77% yield; (iv) NABH /MeOH,
2
4
80% yield; (v) BF /CH Cl , 55% yield or AlCl /CH Cl , 57% yield.
3
2
2
3
2
2
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Intramolecular Cyclization
213
bon d with potassium azodicarboxylate8 (PAD) in AcOH followed by
esterification of th e two h ydroxyls with DCC, Ph CO2H in CH2Cl2 afforded
diben zoate 8 in 66% overall yield. Biooxidation an d reduction with PAD
are described in th e literature8,9
.
cis-Series. Displacem en t of brom in e with oxazolidin e-2,4-dion e in th e
presen ce of 1,1,3,3-tetram eth ylguan idin e (TMG) in THF, followed by reduc-
tion of th e m ore reactive am ide carbon yl with NaBH4 gave th e h em iam in al
9a in 80% yield. Th e N-acylim in ium ion -olefin cyclization was perform ed
with two differen t Lewis acid, BF3·Et2O an d AlCl3 in CH2Cl2 (Sch em e 2).
Th e use of BF3 led to th e isolation of th e perh ydroisoquin olin e 10 in 55%
yield as th e on ly product of th e reaction . With AlCl3 un der th e sam e con di-
tion s, a m ixture of th e isom ers 11a an d 11b was isolated in 57% in a ratio
of 3.7 : 1, respectively (via HPLC). Th e structures of all th ree com poun ds
were determ in ed by X-ray crystallograph y. All th ree com poun ds h ave th e
stereogen ic cen ter C-10b (correspon din g to C-9 of m orph in e) set in th e cor-
rect absolute sen se an d C-10a (C-14 of m orph in e) in th e epi-con figuration .
A proposed m ech an ism for th e BF3-in duced cyclization is outlin ed in
Sch em e 3. After th e in itial form ation of th e carbocation , a n eigh borin g
group participation of th e ben zoate carbon yl10 affords a cis-acetal carbo-
O
O
O
Ph
O
N
N
10b
O
N
O
O
6a
BF
O
BzO
BzO
3
BzO
BzO
HO
7
8
10a
H
H
BzO
O
O
O
Ph
O
N
N
BzO
HO
N
HO
BzO
O
O
O
aqueous
work-up
+
O
H
H
H
H
H
H
BzO
BzO
BzO
SCHEME 3
B
A
cation . Th is in term ediate gave, after aqueous work-up, two cis-fused deriva-
tives A an d/or B. Based on th is m ech an ism , th e products of th e reaction
sh ould h ave a cis relation sh ip between C-6a/C-7 an d C-6a/C-10a. An oth er
in dication th at th e reaction in volves a syn-cyclic tran sition state is th e iso-
lation of product B. Th e stereoch em istry of th e rin g jun ction in 10 is cis, in -
dicatin g n eigh borin g participation of th e ben zoate group in th e cyclization
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

214
Bottari et al.:
step. Th e stereoch em istry of th e rin g jun ction in com poun ds 11a/11b
sh ows th at ch loride can be delivered from both sides of th e m olecule after
th e carbocation is form ed. However, based on th e isom er ratio, we can as-
sum e th at th e Lewis acid coordin ates with th e ben zoate group deliverin g
th e ch loride preferen tially from th e bottom side.
trans-Series. In an attem pt to also set in th e absolute stereoch em istry of
th e stereocen ter C-10a correspon din g to C-14 of n atural m orph in e, we de-
veloped a trans-series an d perform ed th e sam e cyclization reaction in th e
ben zoate-protected diol 17 an d 18 (Sch em e 4). Th e trans-diben zoates were
prepared by th e protection of th e distal h ydroxyl group in diol 12 as a silyl
O
Br
Br
N
O
HO
BzO
(ii)
BzO
(iii)
O
RO
(i)
TBDMSO
1
1
R
14, R = OTBDMS
1
13
12, R = H
12a, R = TBDMS
(iv)
15, R = OH
1
(v)
16, R = OBz
2
O
R
3
R
1
R
N
O
(vi)
(vii)
H
10a
BzO
N
10b
O
HO
H
1
2
3
1
19a, R = R = OH; R = OBz
1
O
R
2
3
19b, R = OH; R = OBz; R = OH
1
1
17, R = OTBDMS
1
2
3
19c, R = OTBDMS; R = OBz; R = OH
1
18, R = OBz
2
3
20a, R = OBz; R = OH; R = OBz
3
1
2
20b, R = OBz; R = OBz; R = OH
1
2
3
21, R = OBz; R = OBz; R = Cl
(i) tert-Butyl(dimethyl)silyl triflate/N,N-diisopropylethylamine/CH Cl , 70% yield; (ii) PhCOOH/DEAD/Bu P/THF,
2
84% yield; (iii) oxazolidione/1,1,3,3-tetramethyguanidine/THF/reflux, 85% yield; (iv) HCl/MeOH, quantitatitative yield;
2
3
.
(v) PhCOOH/DCC/DMAP/CH Cl , 77% yield; (vi) NaBH /MeOH, 77% yield; (vii) BF Et O or AlCl /CH Cl
2
2
2
4
3
2
3
2
SCHEME 4
eth er followed by th e Mitsun obu in version of th e allyl h ydroxyl group to
furn ish 13 in 59% overall yield. Substitution with oxazolidin e-2,4-dion e in
th e presen ce of TMG afforded th e N-acyl derivative 14 in 85% yield.
Deprotection of th e distal silyl eth er in acidic con dition s, followed by
esterification with DCC, Ph CO2H in CH2Cl2 furn ish ed N-acyl diben zoate
protected diol 16 in 77% overall yield from 14. Reduction of th e m ore reac-
tive carbon yl in im ides 14 an d 16 afforded th e precursors for cyclization ,
17 an d 18, respectively.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Intramolecular Cyclization
215
Substrate 17 was th en reacted with BF3·Et2O un der con dition s iden tical to
th ose in th e cis-series an d afforded a com plex m ixture of isom ers. Th e th ree
m ajor products were isolated an d iden tified as 19a, 19b an d 19c in a ratio
of 7.3 : 3.3 : 1, represen tin g 84% of th e total isolated m ass (Sch em e 4). Th e
stereoch em istry of th e isom er 19a was assign ed by X-ray11 an d th e oth ers
by NMR (ref.12). As expected, th e stereoch em istry of th e stereocen ter corre-
spon din g to th e C-14 of n atural m orph in e h as been set in th e absolute
sen se. However, C-10b (C-9 of n atural m orph in e) was set in th e epi-con figu-
ration . Th e iden tification of adduct 19a is in total agreem en t with th e pro-
posed N-acylim in ium ion cyclization m ech an ism described in Sch em e 3.
With th e stereoch em istry at C-10a set in correctly in th e cyclization of
17, an d th e suspicion th at th e silyl eth er group was reactin g with th e BF3
affordin g a com plex m ixture of products, we turn ed to th e cyclization of 18
with BF3 an d AlCl3. As expected, reaction of h ydroxycarbam ate 18 with
BF3·Et2O furn ish ed a clean er m ixture of isom ers. Th e two m ajor isom ers
20a an d 20b (1.4 : 1), represen tin g 70% of th e total isolated m ass of com -
poun ds, were separated (HPLC) an d iden tified (Sch em e 4). Th e
stereoch em istry of both diastereoisom ers was assign ed by X-ray11 an d
2D NMR. Th e isolation of th e adducts con firm ed again th e ben zoate n eigh -
borin g group participation in th e m ech an ism of th e reaction . Wh en th e
sam e substrate was reacted with AlCl3, com poun d 21 was isolated in 70%
yield as th e on ly isom er of th e reaction . Th e stereoch em istry was proven by
X-ray11 an d 2D NMR. Th e stereoch em istry results from th e trans-series bode
well for th e versatility of th e approach to m orph in an s. Sim ple ch em ical
m an ipulation s of tricyclic com poun ds 20a, 20b or 21 can lead to th e syn -
th esis of both m orph in e en an tiom ers. For exam ple, to approach n atural
m orph in e syn th esis, th e stereoch em istry at C-7 an d C-10b would be in -
verted. On th e oth er h an d, C-7 an d C-10b h ave th e correct stereoch em istry
for th e ent-m orph in e syn th esis, provided deh ydroch lorin ation or deh ydra-
tion reaction of C-6a/C-10a is perform ed to in tercept an in term ediate sim i-
lar to 1. In th e cis-series, sim ilar argum en ts also lead to design of im proved
approach es to isoquin olin e derivatives 1 an d 2, suitable for th e n ext gen er-
ation attem pts at m orph in an s.
Acid-catalyzed cyclization of the precursors 9a (cis-series) and 18 (trans-series)
dem on strated good stereoselectivities in th e form ation of stereocen ters
C-6a, C-10a an d C-10b. Th e on ly n oted exception was th e case of 9a wh en
AlCl3 was used, an d 11b was form ed as a m in or product. Th e observed
stereospecificity of th e cyclization reaction s h as im portan t im plication s in
th e stereocon trolled syn th esis of m orph in e an d m orph in e alkaloid deriva-
tives. With th e stereoselective cyclization as th e key step, syn th on s 1 an d 2
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

216
Bottari et al.:
can both be accessed from cyclization precursors 18 an d 9a, respectively.
Th us th e results reported in th is paper con firm ed better preparation of both
1 an d 2. In addition , th e tin -m ediated cyclization of low stereospecificity
reported previously h as been replaced by a m ore en viron m en tally frien dly
acid-catalyzed protocol. Fin ally, in th e fully saturated tricyclic com poun ds
10, 11a, 11b, 20a, 20b an d 21, th e C-14 cen ter of both m orph in e an d
ent-m orph in e can be con trolled at will, albeit at th e expen se of th e corre-
spon din g C-9 stereoch em istry. Th e results of furth er application s will be re-
ported in due course.
The authors thank TDC Research, Inc., NSF (CHE-9315684 and CHE-9521489) and US Environ-
mental Protection Agency (R826113) for financial support of this work.
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Collect. Czech. Chem. Commun. (Vol. 64) (1999)