Advanced intramolecular diels-alder study toward the synthesis of (-)- morphine: Structure correction of a previously reported Diels-Alder product

Article abstract of DOI:10.1055/s-1998-4529

A tricyclic ring system 18 containing all 5 chiral centers of the natural (-)-morphine skeleton has been synthesized in 9 steps. cis-Dienediol 11 was produced by a batch microbial dihydroxylation of (2-azidoethyl)benzene with the E. coli strain JM109(pDTG601). The key step in the synthesis was a thermal [4+2] intramolecular Diels-Alder cycloaddition of triene 16 which afforded the tricyclic adduct 17 in 62% yield. After deprotection, the absolute stereochemistry of the alcohol 18 was determined by X-ray crystallographic analysis. The previously reported Diels-Alder adduct 4a was deprotected and the absolute stereochemistry of the free alcohol was assigned by X-ray crystallography to have the structure 4c. This finding therefore constitutes the correction of the structure for 4a.

Full text of DOI:10.1055/s-1998-4529

March 1998
SYNTHESIS
275
Advanced Intramolecular Diels–Alder Study Toward the Synthesis of (–)-Morphine:
Structure Correction of a Previously Reported Diels–Alder Product
Gabor Butora, Andrew G. Gum, Tomas Hudlicky,* Khalil A. Abboud
Department of Chemistry, University of Florida, Gainesville, FL 32611, U.S.A.
Fax +1(352)8461203; E-mail: hudlicky@chem.ufl.edu
Received 21 May 1997; revised 10 August 1997
Abstract: A tricyclic ring system 18 containing all 5 chiral centers
of the natural (–)-morphine skeleton has been synthesized in 9
steps. cis-Dienediol 11 was produced by a batch microbial dihy-
droxylation of (2-azidoethyl)benzene with the E. coli strain
JM109(pDTG601). The key step in the synthesis was a thermal
[4+2] intramolecular Diels–Alder cycloaddition of triene 16 which
afforded the tricyclic adduct 17 in 62% yield. After deprotection,
the absolute stereochemistry of the alcohol 18 was determined by
X-ray crystallographic analysis. The previously reported Diels–
Alder adduct 4a was deprotected and the absolute stereochemistry
of the free alcohol was assigned by X-ray crystallography to have
the structure 4c. This finding therefore constitutes the correction of
the structure for 4a.
Key words: chemoenzymatic synthesis, (–)-morphine, intramo-
lecular Diels–Alder reaction, X-ray structure proof
Morphine (7), a potent analgesic and arguably the oldest
drug in recorded history, has long been a challenging tar-
get for synthetic chemists. In spite of the previously re-
ported 17 total or formal syntheses of morphine,1–17
a
truly practical synthesis, which would rival the economy
of isolation from natural opium, continues to elude the
synthetic community. Although none of the total or for-
mal syntheses of morphine relied on a [4+2] cycloaddition
as the pivotal step, several successful attempts at morphi-
nan syntheses utilizing intramolecular Diels–Alder meth-
odology have been published.18–22
Scheme 1
In 1992, we published a model study23 that employed a
a: (i) potassium azodicarboxylate (PAD), HOAc, MeOH; (ii) THS-Cl,
Diels–Alder cyclization or a Diels–Alder and Cope rear- imidazole, DMF; (iii) NaH, sorbyl bromide, THF. b: (i) THS-Cl, imi-
dazole, DMF; (ii) NaH, sorbyl bromide, THF. c: toluene, sealed tube.
210°C, 24 h. d: (i) CCl4, reflux, 7 h; (ii) Bu4NF 3 H2O, THF, r.t.,
rangement sequence to obtain tricycles 4a and 6 respec-
tively (Scheme 1). The stereochemistry of 4a and 6 was
deduced from NOE correlations, but the two structures
have not been converted to a common intermediate for un-
ambiguous comparison. In this paper, we report an ad-
vanced Diels–Alder study and concomitant correction of
the structure 4a to that of 4b via its free alcohol 4c.
•
24 h; (iii) PCC, CH2Cl2, r.t., 24 h. e: HF/MeCN (5:95), 12 h. f: (i) xyle-
•
nes, sealed tube, 250°C; (ii) NaBH4, CeCl3 7 H2O, MeOH, r.t., 15 min.
On the assumption that the tricycle 4a was produced ste-
reoselectively via the endo transition state (Scheme 1), we
turned to the advanced model study in which a leaving
group at the incipient C9 of morphine 7 would be dis-
placed by a nucleophilic nitrogen at C16 to form the
bridged product 8 (Figure). Before committing to the ha-
lide 9b or tosylate 9c, we set out to synthesize model com-
Figure. Retrosynthetic Analysis
pound 9a by analogous Diels–Alder methodology. The
late) afforded diol 12. Alternatively, diol 12 was obtained
methyl-substituted diene provided the simplest model for
in a more laborious procedure by microbial dihydroxyla-
establishing the stereochemical outcome of the cycloaddi-
tion of (2-bromoethyl)benzene (10a) (10 g/L),25 followed
tion of a terminally functionalized diene ether.
by diimide reduction, and protection as the acetonide. Dis-
Whole cell biooxidation of (2-azidoethyl)benzene (10b),
easily synthesized from commercially available (2-bro-
moethyl)benzene (10a), readily afforded cis-dienedio] 11
stereospecifically and in good yield of approximately 6 g/
placement of the bromide with sodium azide followed by
acetonide cleavage afforded free diol 12.24 Selective pro-
tection of the homoallylic hydroxy group yielded silyl
ether 13. Alkylation of the allylic oxygen upon exposure
of its sodium alkoxide to sorbyl bromide26 gave triene 14.
The azide was reduced to amine 15 and converted to acet-
L
24 (Scheme 2). Reduction of the less substituted olefin
with diimide (generated from potassium azodicarboxy-

276
Papers
SYNTHESIS
amide 16. The resulting triene 16 was cyclized under con- available.24 For possible endo transition states, the place-
ditions similar to those by which 4a was prepared23 to ment of leaving groups and nucleophiles will be switched
afford the cycloadduct 17 as a single stereoisomer in 62% between C9 and C16. Finally, the use of E,Z-dienes
yield. Since an unambiguous assignment of the absolute equipped with terminal leaving groups (Cl, OTs, etc.)
stereochemistry by spectroscopy was not possible, a sin- would provide additional flexibility in controlling the ste-
gle crystal of the alcohol 18, obtained by deprotection of reochemistry for the nucleophilic displacement and con-
tricycle 17, was grown. X-ray crystallographic analysis struction of the bridge. The preparation of compounds of
confirmed the stereochemistry of the cycloadduct 18 as type 9b via cycloadditions of E,Z-halodienes is currently
shown27 and indicated that the [4+2] cycloaddition pro- under way and will be reported in due course.
ceeded via an exo transition state.
All non-hydrolytic reactions were performed in solvents either dried
according to standard procedures or purchased from Aldrich. Analyt-
ical TLC was performed on silica gel 60F-254 (Whatman). Flash
chromatograaphy was performed on Fisher silica gel (grade 60, 200–
425 mesh). 1H NMR spectra were recorded on a Varian VXR-300 and
13C multiplicities were determined by APT experiments. MS were re-
corded on a Finnigan Mat 95 Q mass spectrometer. IR spectra were
obtained on a Perkin Elmer 1600 Series instrument. Optical rotations
were measured on a Perkin Elmer 341 polarimeter. Mps were ob-
tained on a Thomas Hoover Uni-melt apparatus.
(2aS,5R,5aS,8S,8aR,8bS)-5,8b-Dimethyl-2a,5,5a,6,7,8,8a,8b-octa-
hydro-2H-benzo[cd]isobenzofuran-8-ol (4c):
To a solution of tricyclic silyl ether 4b (74 mg, 0.24 mmol) in MeCN
(9.5 mL) was added 48% aq HF (0.5 mL). The reaction mixture was
stirred for 12 h at r.t. Water (40 mL) was added, the aqueous phase
was neutralized with 10% NaOH and extracted with Et2O (3 ´
25 mL). The combined organic phases were washed with brine and
dried (MgSO4). After concentration by rotary evaporation, the crude
product was purified by flash column chromatography (4:1 hexanes/
EtOAc) to afford the tricyclic alcohol 4c (32 mg, 73%) as a colorless,
viscous oil which crystallized from CDCl3 by slow evaporation to ob-
tain single crystals for X-ray analysis; Rf = 0.20 (4:1 hexanes/EtOAc).
IR (CHCl3): n = 3420, 3020, 2960, 2930, 2870, 1210 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.63 (dt, J = 9.5, 2.2 Hz, 1H), 5.56
(dt, J = 9.5, 2.2 Hz, 1H), 4.12 (t, J = 7.6 Hz, 1H), 3.90 (m, 1H), 3.64
(m, 2H), 3.02 (m, 1H), 2.51 (s, 1H), 1.90 (m, 2H), 1.62 (m, 1H), 1.38
(m, 3H), 1.12 (d, J = 7.6 Hz, 3H), 0.88 (s, 3H).
Scheme 2
a: NaN3, DMF. b: E. coli
JM109(pDTG601). c: PAD, HOAc, MeOH, 0°C–r.t., 14 h. d: THS-
Cl, imidazole, DMF, 0°C, 13 h. e: NaH, sorbyl bromide, THF, 0 °C-
r.t., 14 h. f: PPh3. 0.4% H2O/THF, 45 °C 18 h. g: Ac2O, pyridine, r.t.,
2 h. h: toluene, sealed tube, 230°C, 20 h. i: HF/MeCN (5:95), r.t., 3.5 h.
13C NMR (75 MHz, CDCl3): d = 135.0 (CH), 122.3 (CH), 84.2 (CH),
69.6 (CH2), 66.4 (CH), 47.7 (CH), 42.9 (CH2), 39.6 (CH3), 37.3
(CH3), 28.5 (CH2), 23.2 (CH), 23.= (CH), 22.7 (CH2).
On the basis of this observation, we reinvestigated the ste-
reochemical assignment of the reported endo cycloadduct
4a by X-ray crystallography of its free alcohol and con-
firmed this structure as 4c,28 therefore proving that the in-
tramolecular Diels–Alder reaction proceeded in an exo
fashion to afford both 18 and 4c. This result serves as a
formal structure correction of cycloadduct 4a.
The combination of enzymatic chemistry and a stereospe-
cific intramolecular Diels–Alder reaction allowed for the
efficient synthesis of tricycle 18, which contains all of the
stereocenters of natural (–)-morphine in the correct abso-
lute configuration. It is noteworthy that the intramolecular
Diels–Alder cyclization led to the correct stereochemistry
of both C14 and C9 of morphine, a feat not simultaneously
attained by most of the previously reported strategies.
HRMS: 209.1504 (C13H20O2+H) requires 209.1541.
(1S,2R)-3-(2-Azidoethyl)cyclohex-3-ene-1,2-diol (12):
To a solution of azidodienediol 11 (~35 g, 0.19 mol) in MeOH
(300 mL) was added potassium azodicarboxylate (PAD, 85 g,
0.44 mol). The suspension was cooled to 0 °C, and a mixture of HOAc
(50 mL) and MeOH (100 mL) was added dropwise over 2 h. The so-
lution was allowed to warm to r.t. and continued stirring for 14 h. Ad-
ditional HOAc (10 mL) was added to decompose any excess PAD,
and the mixture was concentrated by rotary evaporation. Water (150
mL) was added and the crude product was extracted into CH2Cl2 (5 ´
50 mL). The combined organic layers were washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The remaining
solid was recrystallized (CH2Cl2/hexanes) to afford diol 12 (25 g,
72%) as a white crystalline material; mp 54–55 °C; Rf = 0.13 (1:1,
hexane/EtOAc); [a]D29 –98.5 (c = 1.0, CHCl3).
In light of the stereochemical outcome of the Diels–Alder
reaction, it is clear that our next strategy must focus on a
flexible approach to accommodate the exo versus endo
Anal. Found: C, 52.47; H, 7.09; N, 22.78. C8H13O2N3 requires: C,
52.43; H, 7.16; N, 22.94.
options in the [4+2] cycloaddition. If the E,E-dienes con- IR (KBr): n = 3280, 2940, 2095, 1260, 1080 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.66 (bs, 1H), 3.99 (d, J = 3.4 Hz,
tinue to produce the b-C9 stereochemistry via the exo tran-
sition state in the thermal cycloaddition, then C9 will need
to contain a nucleophilic nitrogen while a leaving group
will be installed at C16 (see numbering in morphine 7) that
is on the ethyl side chain of diols such as 11. Several such
compounds (X=OH, OAc, etc.) have recently become
1H), 3.75 (m, 1H), 3.40 (t, J = 7 Hz, 2H), 2.96 (s, 2H), 2.40 (m, 2H),
2.16 (m, 1H), 2.08 (m, 1H), 1.70 (m, 2H).
13C NMR (75 MHz, CDCl3): d = 133.9 (C), 128.1 (CH), 69.5 (CH),
68.6 (CH), 50.1 (CH2), 34.0 (CH2), 25.1 (CH2), 23.9 (CH2).
MS (EI): m/z (%) = 184 (M+, 8), 138 (42), 120 (100).
HRMS: 184.1153, (C8H13O2N3+H) requires 184.1086.

March 1998
SYNTHESIS
277
(1R,6S)-2-(2-Azidoethyl)-6-(dimethylthexylsiloxy)cyclohex-2-en-
1-ol (13):
2H), 2.02 (m, 1H), 1.94 (m, 1H), 1.72 (d, J = 6.8 Hz, 3H), 1.66 (sept,
J = 6.8 Hz, 1H), 1.57 (m, 1H), 1.38 (bs, 2H), 0.90 (s, 3H), 0.88 (s, 3H),
To a cooled (0°C) solution of diol 12 (122 mg, 0.67 mmol) in DMF 0.84 (s, 6H), 0.12 (s, 6H).
(0.75 mL) was added imidazole (54 mg, 0.80 mmol) followed by 13C NMR (75 MHz, CDCl3): d = 134.7 (C), 132.7 (CH), 130.9 (CH),
THS-Cl (142 mg, 0.80 mmol). The mixture was stirred briefly and al- 129.5 (CH), 128.0 (CH), 126.3 (CH), 77.3 (CH), 73.2 (CH2), 72.6
lowed to stand at 0 °C for 13 h. Water (40 mL) was added and the (CH), 40.4 (CH2), 39.2 (CH2), 34.0 (CH3), 25.6 (CH2), 25.0 (C), 24.9
aqueous layer was extracted with Et2O (3 ´ 15 mL). The combined or- (CH2), 20.3 (CH3), 20.2 (CH3), 18.6 (CH3), 18.5 (CH3), –2.6
ganic layers were dried (MgSO4) and concentrated under reduced (2 ´ CH3).
pressure. The crude product was purified by column chromatography HRMS: 380.2977, (C22H41O2NSi+H) requires 380.2984.
(9:1 hexane/EtOAc) to afford 13 (214 mg, 99%) as a colorless oil; Rf
= 0.49 (9:1 hexane/EtOAc); [a]D26 –37.0 (c = 1.2, CHCl3).
(5S,6R)-1-(2-Acetamidoethyl)-5-(dimethylthexylsiloxy)-6-
[(2E,4E)-hexa-2,4-dienyloxy]cyclohex-1-ene (16):
Anal. Found: C, 59.11; H, 9.64; N, 12.84. C16H31O2N3Si requires: C,
59.04; H, 9.60; N, 12.91.
To a solution of amine 15 (263 mg, 0.69 mmol) in pyridine (2 mL)
IR (CHCl3): n = 3550, 2950, 2095, 1460, 1370, 1250, 1080 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.65 (bs, 1H), 3.89 (bs, 1H), 3.81
(dt, J = 10.7, 3.9 Hz, 1H), 3.41 (m, 2H), 2.66 (d, J = 2.7 Hz, 1H), 2.42
(m, 2H), 2.17 (m, 1H), 2.02 (m, 1H), 1.77 (m, 1H), 1.63 (sept, J = 6.9
Hz, 1H), 1.55 (m, 1H), 0.89 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz,
3H), 0.85 (s, 6H), 0.14 (s, 3H), 0.13 (s, 3H).
was added Ac2O (106 mg, 1.04 mmol), and the mixture was stirred at
r.t. for 2 h. The solvent was removed by rotary evaporation, and the
crude product was purified by column chromatography (100%
EtOAc) to afford the amide 16 (259 mg, 89%) as a colorless, viscous
oil; Rf = 0.69 (EtOAc fully saturated with NH4OH); [a]D28 –78.9 (c =
1.15, CHCl3).
13C NMR (75 MHz, CDCl3): d = 133.7 (C), 127.6 (CH), 70.8 (CH),
68.8 (CH), 50.0 (CH2), 34.5 (CH2), 34.2 (CH), 25.3 (CH2), 24.9 (C),
24.1 (CH2), 20.3 (CH3), 20.2 (CH3), 18.6 (CH3), 18.5 (CH3), –2.4
(CH3), –3.0 (CH3).
IR (CHCl3): n = 3450, 3020, 2980, 2900, 1660, 1520, 1220, 1050 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.18 (dd, J = 14.8, 10.2 Hz, 1H),
6.03 (ddd, J = 14.8, 10.4, 1.7 Hz, 1H), 5.67 (m, 2H), 5.51 (bs, 1H),
4.52 (dd, J = 11.8, 6.0 Hz, 1H), 4.05 (dd, J = 11.8, 7.0 Hz, 1H), 3.83
(dt, J = 10.7, 3.3 Hz, 1H), 3.61 (d, J = 2.8 Hz, 1H), 3.31 (m, 2H), 2.32
(m, 1H), 2.10 (m, 3H), 1.92 (m, 1H), 1.89 (s, 3H), 1.74 (d, J = 6.9 Hz,
3H), 1.64 (sept, J = 6.9 Hz, 1H), 1.56 (m, 1H), 0.89 (s, 3H), 0,88 (s,
3H), 0.84 (s, 6H), 0.12 (s, 3H), 0.11 (s, 3H).
MS (EI) m/z (%) = 308 (M-H2O+, 45), 280 (100).
(5S,6R)-1-(2-Azidoethyl)-5-(dimethylthexylsiloxy)-6-[(2E,4E)-
hexa-2,4-dienyloxy]cyclohex-1-ene (14):
To a cooled (0°C) suspension of 60% NaH in mineral oil (117 mg,
2.92 mmol) in THF (1 mL) was added dropwise a solution of the
mono protected azide 13 (476 mg, 1.46 mmol) in THF (2 mL). The
mixture stirred at 0°C for 20 min. A solution of sorbyl bromide
(353 mg, 2.19 mmol) in THF (1 mL) was added dropwise. The cool-
ing bath was removed and the mixture was stirred for 14 h. Water
(70 mL) was added and the crude product was extracted into Et2O
(3 ´ 30 mL). The combined organic layers were washed with brine
and dried (MgSO4). Removal of solvent under reduced pressure gave
a crude product which was purified by repeated column chromatogra-
phy (99:1 hexane/EtOAc) [note: 3 separate columns were necessary
to separate the product from unreacted sorbyl bromide] to afford 14
as a pale yellow oil (344 mg, 58%); Rf = 0.61 (95:5 hexane/EtOAc);
[a]D26 –53.2 (c = 1.11, CHCl3).
13C NMR (75 MHz, CDCl3): d = 170.0 (C), 134.1 (C), 133.4 (CH),
130.8 (CH), 130.2 (CH), 127.4 (CH), 127.2 (CH), 77.9 (CH), 73.0
(CH2), 71.9 (CH), 38.7 (CH2), 34.3 (CH2), 34.0 (CH3), 25.8 (CH2),
24.9 (C), 24.7 (CH2), 23.3 (CH), 20.4 (CH3), 20.2 (CH3), 18.6 (CH3),
18.5 (CH3), –2.6 (2 ´ CH3).
MS (FAB): m/z (%) = 422 (M+H+, 4), 324 (86), 265 (98).
HRMS: 422.3056, (C24H43O3NSi+H) requires 422.3090.
(2aS,5R,5aS,8S,8aR,8bS)-8b-(2-Acetamidoethyl)-8-(dimethyl-
thexylsiloxy)-5-methyl-2a,5,5a,6,7,8,8a,8b-octahydro-2H-ben-
zo[cd]isobenzofuran (17):
A solution of triene 16 (126 mg, 0.299 mmol) in toluene (15 mL) was
placed in a thick-wall glass reaction tube equipped with a Teflon
screw cap. The reaction mixture was degassed using 3 repeated
freeze-pump-thaw cycles, lowering the reaction tube’s temperature to
–78 °C at the start of each cycle, and sealed under argon. The reaction
tube was placed in a sand bath preheated to 230 °C. After 20 h, the
tube was cooled in a liquid nitrogen bath, carefully opened, and the
contents removed. The toluene was distilled off under reduced pres-
sure, and the crude product was purified by column chromatography
(100% EtOAc) to afford the tricycle 17 (78 mg, 62%) as a colorless
oil. Crystallization from hexanes afforded colorless crystals; mp 123–
124°C; Rf = 0.21 (100% EtOAc); [a]D26 +11.0 (c = 1.0, CHCl3).
IR (CHCl3): n = 2950, 2870, 2095, 1460, 1380, 1250, 1100 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.17 (dd, J = 14.8, 10.2 Hz, 1H),
6.05 (ddd, J = 14.7, 10.4, 1.7 Hz, 1H), 5.68 (m, 2H), 5.55 (bs, 1H),
4.46 (dd, J = 12.1, 5.8 Hz, 1H), 4.09 (dd, J = 12.1, 7.1 Hz, 1H), 3.82
(dt, J = 11.0, 3.0 Hz, 1H), 3.64 (d, J = 3.0 Hz, 1H), 3.33 (m, 2H), 2.34
(m, 2H), 2. 18 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H), 1.75 (d, J = 6.6
Hz, 3H), 1.66 (sept, J = 6.8 Hz, 1H), 1.58 (m, 1H), 0.91 (s, 3H), 0.89
(s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.12 (s, 6H).
13C NMR (75 MHz, CDCl3): d = 133.5 (C), 133.0 (CH), 130.9 (CH),
129.8 (CH), 127.7 (CH), 127.3 (CH), 76.9 (CH), 73.0 (CH2), 71.9
(CH), 50.2 (CH2), 34.1 (CH2), 34.0 (CH3), 25.7 (CH2), 24.9 (C), 24.8
(CH2), 20.3 (2 x CH3), 18.6 (CH3), 18.1 (CH3), –2.6 (2 ´ CH3).
HRMS: 406.2824, (C22H39O2N3Si+H) requires 406.2889.
Anal. Found: C, 67.85; H, 10.03; N, 3.24. (C24H43NO3Si) requires: C,
68.36; H, 10.28; N, 3.32. (Best result obtained after repeated analyses
of recrystallized product.)
IR (KBr): n = 3240, 2960, 2860, 1640, 1560, 1440, 1380, 1250,
(5S,6R)-1-(2-Aminoethyl)-5-(dimethylthexylsiloxy)-6-[(2E,4E)-
hexa-2,4-dienyloxy]cyclohex-1-ene (15):
1080 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.64 (dt, J = 9.6, 2.8 Hz, 1H), 5.57
(dt, J = 9.6, 2.8 Hz, 1H), 5.44 (bs, 1H), 4.10 (dd, J = 8.8, 6.9 Hz, 1H),
3.95 (t, J = 3.6 Hz, 1H), 3.71 (d, J = 5.2 Hz, 1H), 3.54 (dd, J = 11.5,
6.9 Hz, 1H), 3.42 (m, 1H), 3.29 (m, 1H), 3.12 (m, 1H), 1.94 (s, 3H),
1.90 (m, 1H), 1.64 (m, 5H), 1.44 (m, 1H), 1.27 (m, 2H), 1.14 (d, J =
7.7 Hz, 3H), 0.87 (d, J = 6.9 Hz, 6H), 0.83 (s, 6H), 0.12 (s, 3H), 0.08
(s, 3H).
To a solution of azide 14 (106 mg, 0.26 mmol) in THF (10 mL) was
added PPh3(102.8 mg, 0.39 mmol) and water (0.04 mL). After stirring
at 45 °C for 18 h, the mixture was concentrated under reduced pres-
sure and the crude product was purified by column chromatography
(EtOAc-50% saturated with NH4OH) [note: The eluent was prepared
by diluting EtOAc fully saturated with NH4OH with an equal volume
of 100% EtOAc] to afford the amine 15 as a pale yellow oil (65 mg,
66%); Rf = 0.71 (7:3: 1 EtOAc/ EtOH/NH4OH); [a]D28 –72.5 (c = 1.22,
CHCl3).
13C NMR (75 MHz, CDCl3): d = 169.9 (C), 135.1 (CH), 123.2 (CH),
79.8 (CH), 68.6 (CH2), 68.1 (CH), 45.9 (C), 42.7 (CH), 40.0 (CH),
37.4 (CH), 35.8 (CH2), 34.0 (CH), 31.4 (CH2), 30.1 (CH2), 24.8 (C),
23.3 (CH3), 23.0 (CH3), 22.9 (CH2), 20.2 (2 ´ CH3), 19.0 (CH3), 18.5
(CH3), –2.6 (CH3), –3.2 (CH3).
IR (CHCl3): n = 3020, 2960, 2870, 1220, 1090 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.15 (dd, J = 14.9, 10.5 Hz, 1H),
6.05 (ddd, J = 14.4, 9.0, 1.5 Hz, 1H), 5.66 (m, 2H), 5.46 (s, 1H), 4.46
(dd, J = 12.5, 6.1 Hz, 1H), 4.08 (dd, J = 11.7, 6.8 Hz, 1H), 3.78 (dt, J
= 11.2, 3.2 Hz, 1H), 3.58 (d, J = 2.7 Hz, 1H), 2.76 (m, 2H), 2.18 (m,
MS (FAB) m/z = 422 (M+H)+.
HRMS: 422.3056, (C24H43O3NSi+H) requires, 422.3090.

278
Papers
SYNTHESIS
(2aS,5R,5aS,8S,8aR,8bS)-8b-(2-Acetamidoethyl)-5-methyl-
2a,5,5a,6,7,8,8a,8b-octahydro-2H-benzo[cd]isobenzofuran-8-ol
(18):
(8) Rice, K. C. J. Org. Chem. 1980, 45, 3135.
(9) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285.
(10) Moos, W. H.; Gless, R. D.; Rapoport, H. J. J. Org. Chem. 1983,
48, 227.
(11) White, J. D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K.
C.; Brossi, A. Tetrahedron 1983, 39, 2393.
To a solution of tricycle 17 (90 mg, 0.21 mmol) in MeCN (9.5 mL)
was added 45% aq HF (0.5 mL). The mixture was stirred at r.t. for
1.5 h and another portion of 45% aq HF (0.5 mL) was added. After
stirring an additional 2 h, the mixture was neutralized with 10%
NaOH and extracted with Et2O (3 ´ 10 mL), The combined organic
layers were dried (MgSO4) and concentrated under reduced pressure.
The crude product was purified by column chromatography (95:5
EtOAc/MeOH) to obtain the alcohol 18 (24 mg, 65%) as a colorless,
viscous oil. Crystallization from CDCl3 (the solution was allowed to
evaporate slowly from a capped tube at r.t. over several weeks) af-
forded single crystals suitable for X-ray analysis; mp 186–188 °C; Rf
= 0.21 (95:5 EtOAc/MeOH); [a]D29 +5.75 (c = 0.4, CHCl3).
Anal. Found: C, 68.59; H, 8.98, N, 5.03. (C16H25NO3) requires C,
68.79; H, 9.02; N, 5.01.
(12) Ludwig, W.; Schäfer, H. J. Angew. Chem., Int. Ed. Engl. 1986,
25, 1025.
(13) Toth, J. E.; Fuchs, P. L. J. Org. Chem. 1987, 52, 473.
(14) Tius, M. A.; Kerr, M. A. J. Am. Chem. Soc. 1992, 114, 5959.
(15) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688.
(16) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993,
115, 11028.
(17) Mulzer, J.; Dürner, G.; Trauner, D, Angew. Chem. 1996, 108,
3046; Angew. Chem., Int. Ed. Engl. 1996, 35, 2830.
(18) Ciganek, E. J. Am. Chem. Soc., 1981, 103, 6261.
(19) Handa, S.; Jones, K.; Newton, C. G.; Williams, D. J. J. Chem.
Soc., Chem. Commun. 1985, 1362.
IR (neat) n = 3680, 3020, 2980, 1730, 1670, 1520, 1420, 1210, 1050
cm–1.
(20) Kametani, T.; Suzuki, Y.; Honda, T. J. Chem. Soc., Perkin
Trans. 1 1986, 1373.
1H NMR (300 MHz, CDCl3): d = 5.60 (bs, 1H), 5.49 (bs, 1H), 4.15 (t,
J = 8.3 Hz, 1H), 3.94 (m, 1H), 3.85 (d, J = 5.6 Hz, 1H), 3.63 (dd, J =
12.0, 7.6, Hz, 1H), 3.41 (m, 1H), 3.18 (m, 2H), 2.21 (bs, 1H), 1.94 (s,
3H), 1.90 (bs, 1H), 1.68 (m, 3H), 1.43 (m, 1H), 1.26 (m, 3H), 1.15 (d,
J = 7.8 Hz, 3H).
(21) Constanzo, M. J. Ph. D. Thesis, Temple University, 1988.
(22) Wu, C. Ph. D. Thesis, Columbia University, 1990.
(23) Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174.
(24) Hudlicky, T.; Endoma, M. A. A.; Butora, G. J. Chem. Soc., Per-
kin Trans. 1 1996, 2187.
(25) Stabile, M. R.; Hudlicky, T.; Meisels, M. L. Tetrahedron
Asymmetry 1995, 6, 537.
(26) Mori, K. Tetrahedron 1974, 30, 3807.
13C NMR (75 MHz, CDCl3): d = 170.0 (C), 135.5 (CH), 122.0 (CH),
80.2 (CH), 69.2 (C), 66.5 (CH), 45.5 (C), 42.4 (CH), 40.6 (CH), 37.4
(CH), 35.8 (CH2), 31.2 (CH2), 28.3 (CH2), 23.3 (CH3), 22.9 (CH3),
22.6 (CH2).
MS (CI/methane): m/z (%) = 280 (M+H+, 100), 262 (35).
HRMS: 280.1959, (C16H25NO3+H) requires 280.1912.
(27) X-ray data for 18: C16H25NO3, Mr = 279.37, Orthorhombic,
P212121, a = 7.6014(1) Å, b = 10.6199(3) Å, c = 18.8051(6) Å,
V = 1518.06(7) Å3, Z = 4, Dcalc. = 1.222 g cm–3, Mo Ka (l =
0.71073 A), T = 173 K. The structure was solved by the Direct
Methods in SHELXTL5, and refined using full-matrix least
squares. The non-H atoms were treated anisotropically. The hy-
drogen atoms were obtained from a Diffference Fourier map and
refined without constraints. 282 parameters were refined in the
final cycle of refinement using 2530 reflections with I > 2s(I)
to yield R1 and wR2 of 3.87 and 7.41%, respectively. Refine-
ment was done using F2.
(28) X-ray data for 4c: C13H20O2, Mr = 208.29, Orthorhombic,
P212121, a = 6.2053(2) Å, b = 1386542(1) Å, c = 13.8944(4) Å,
V = 1177.25(5) Å3, Z = 4, Dcalc. = 1.175 g cm–3, Mo Ka (l =
0.71073 Å), T = 173 K. The structure was solved by the Direct
Methods in SHELXTL5, and refined using full-matrix least
squares. The non-H atoms were treated anisotropically. The hy-
drogen atoms were obtained from a Diffference Fourier map and
refined without constraints. 217 parameters were refined in the
final cycle of refinement using 2236 reflections with I > 2s(I)
to yield R1 and wR2 of 4.26 and 9.15%, respectively. Refine-
ment was done using F2.
The authors wish to thank the National Science Foundation, TDC
Research, Inc., and the University of Florida for funding. K.A.A.
wishes to acknowledge the National Science Foundation for funding
of the purchase of the X-ray equipment.
(1) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1954, 78, 1380.
(2) Elad, D.; Ginsburg, D. J. Am. Chem. Soc. 1954, 76, 312.
(3) Barton, D. H. R.; Kirby, G. W.; Steglich, W.; Thomas, G. M.
Proc. Chem. Soc., London 1963, 203.
(4) Morrison, G. C.; Waite, R. P.; Shavel, J. Jr. Tetrahedron Lett.
1967, 4055.
Grewe, R.; Friedrichsen, W. Chem. Ber. 1967, 100, 1550.
(5) Kametani, T.; Ihara, M.; Fukumoto, K.; Yagi, H. J. Chem. Soc.,
Chem. Commun. 1969, 2030.
(6) Schwartz, M. A.; Mami, I. S. J. Am. Chem. Soc. 1975, 97, 1239.
Schwartz, M. A.; Pham, P. T. K. J. Org. Chem. 1988, 53, 2318.
(7) Lie, T. S.; Maat, L.; Beyerman, H. C. Recl. Trav. Chim. Pays-
Bas 1979, 98, 419.
Sheldrick, G. M. (1995). SHELXTL5. Siemens Analytical In-
strumentation, Madison, Wisconsin, USA.