Synthesis of n-containing drimane sesquiterpenoids from 11-dihomodriman-8α-ol-12-one

Article abstract of DOI:10.1007/s10600-010-9671-9

Beckmann reaction products of 11-dihomodriman-8α-ol-12-one oxime with Ac2O in pyridine, 86% H₃PO₄, p-TsCl in pyridine, and PCl₅ in ether were investigated. It has been found that the major product from treatment of the oxime with Ac₂O is the oxime acetate. Reaction of the oxime with 86% H₃PO₄ gave (1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-1H-naphtho[1,2][5,6]-3-methyl-4, 5-dihydro[1,2,6]oxazine; with p-TsCl, (1S,2S,4aS,8aS)-2,5,5,8a- tetramethyldecahydro-1H-naphtho[1,2][5,6]-2-methyl-4,5- dihydro[1,3,6]oxazine; with PCl₅, a mixture of products containing 11-acetylamino- and 11-methylaminooxodrimenes that were isomeric at the double bond, norambreinolide, and a 1,3,6-oxazine.

Full text of DOI:10.1007/s10600-010-9671-9

Chemistry of Natural Compounds, Vol. 46, No. 4, 2010
SYNTHESIS OF N-CONTAINING DRIMANE SESQUITERPENOIDS
FROM 11-DIHOMODRIMAN-8ꢀ-OL-12-ONE
1*
1
1
K. I. Kuchkova, A. N. Aryku, P. F. Vlad,
UDC 577.547.91
2,3
3
K. Deleanu, and A. Nikolescu
Beckmann reaction products of 11-dihomodriman-8ꢀ-ol-12-one oxime with Ac O in pyridine, 86% H PO ,
2
3
4
p-TsCl in pyridine, and PCl in ether were investigated. It has been found that the major product from
5
treatment of the oxime with Ac O is the oxime acetate. Reaction of the oxime with 86% H PO gave
2
3
4
(1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-1H-naphtho[1,2][5,6]-3-methyl-4,5-dihydro[1,2,6]oxazine;
with p-TsCl, (1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-1H-naphtho[1,2][5,6]-2-methyl-4,5-
dihydro[1,3,6]oxazine; with PCl , a mixture of products containing 11-acetylamino- and 11-methylamino-
5
oxodrimenes that were isomeric at the double bond, norambreinolide, and a 1,3,6-oxazine.
Keywords: Beckmann rearrangement, synthesis, drimane sesquiterpenoids, 11-dihomodriman-8ꢀ-ol-12-one, oxazine.
Nitrogen-containing drimanes and their biological activity represent a poorly studied area of terpenoid chemistry.
Therefore, the synthesis of such compounds is of scientific interest.
The preparation of amides 1–4 via Beckmann rearrangement of the Z- and E-isomers of oxime 5 of 14,15-dinorlabd-
8(17)-en-13-one (6) was reported earlier [1]. Amulti-step synthesis of amide 7 from (-)-sclareol that uses the natural sesquiterpene
drim-9,11-en-8ꢀ-ol (8) as an intermediate in the synthesis was described [2].
NHCH
CH
3
3
NHCOCH
NHCOCH
OH
3
3
O
R
4
5, 6
5: R = NOH; 6: R = O
1, 2
1: ꢁ8,9; 2: ꢁ8,17
3
O
NHCOCH
12
3
11
9
15
O
1
4
OH
OH
5
7
14
13
7
8
11
Our goal was to study the synthesis of 7 via Beckmann rearrangement of oxime 9 of 11-dihomodriman-8ꢀ-ol-12-one
(10). Hydroxyketone 10 is readily available and can be obtained from norambreinolide (11) by the method described by us
[3]. Oxime 9 was prepared from 10 by reaction with NH OH4HCl in a mixture of EtOH and Py. It was a mixture of the Z- and
2
1
13
15
E-isomers according to TLC and H, C, and N NMR spectra. Because the Z-isomer can be easily converted to the
E-isomer and the latter is energetically more favorable [1, 4], we used 9 for the reactions as a mixture of its Z- and E-isomers.
The Beckmann rearrangement is known to occur stereospecifically as a result of anti-migration of the bulkier radical. Therefore,
it was expected that the major product of the Beckmann rearrangement of 9 would be amide 7.
1) Institute of Chemistry, Academy of Sciences, Republic of Moldova, MD-2028, Kishinev, fax: (3732) 73 97 75,
e-mail: vlad_p@mail.md; 2) Institute of Organic Chemistry of the Romanian Academy, RO-71141, Bucharest, Romania, fax:
(401) 627 63 66, e-mail: calind@fx.ro; 3) P. Poni Institute of Macromolecular Chemistry of the Romanian Academy, 700487,
Yassy, Aleea Grigore Gika Vode, 41 A, Romania. Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 456–460, July–
August, 2010. Original article submitted March 10, 2009.
©
0009-3130/10/4604-0539 2010 Springer Science+Business Media, Inc.
539

13
12
11
N
N
OCOCH
3
17
R
N
OCOCH
3
14
86% H PO
Ac O/Py
2
O
3
4
1
4
10
8
+
OH
OH
60 - 70 °C
82%
105 - 110 °C
6
15
16
12 (90%)
13 - 15
16
10: R = O
.
13:ꢁ7,8
14:ꢁ8,14
15:ꢁ8,9
NH OH HCl
2
EtOH, Py
9: R = N-OH (94%)
5%
p-TsCl
Py, 90%
.
p-TsOH
N CH
N
CH
3
NHCOCH
3
3
C
C
N
OTs
O
O
CH CN, ꢁ
p-TsOH
95%
10% KOH
3
OH
- p-TsOH
MeOH
95%
- H O
2
17
18
19
20
Al O
2
3
58%
Scheme 1
We reacted 9 with Ac O in Py, 86% H PO , p-TsCl in Py, and PCl in Et O in order to achieve our goal. A study of
2
3
4
5
2
the products showed that treatment of 9 with Ac O in Py at 105–110°C did not cause rearrangement but gave oxime acetate 12
2
as the major product (90% yield) and a small amount of a mixture of three isomers of dehydrated oxime acetate 13–15 in a
50:39:11 ratio (5% yield) (Scheme 1).
Oxime acetate 12 was a mixture of the Z- and E-isomers in a 1:4.9 ratio. One of the isomers with the smaller R value
f
(TLC) was isolated as pure crystals. It was proven earlier [1] using the oxime of 14,15-dinorlabd-8(17)-en-13-one (5) as an
example that the isomer with the greater Rf value has the E-configuration; with the smaller value, the Z-configuration. Therefore,
by analogy the crystalline isomer of 12 can be assigned the Z-configuration. Heating a solution of 9 in 86% H PO also did
3
4
not cause a Beckmann rearrangement but dehydration and cyclization gave (1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-
1H-naphtho[1,2][5,6]-3-methyl-4,5-dihydro[1,2,6]oxazine (16) (Scheme 1).
Reaction of 9 with p-TsCl in Py at room temperature gave the oxime tosylate 17, which underwent Beckmann
rearrangement upon brief refluxing in CH CN with subsequent loss of water and p-toluenesulfonic acid to form amide 18 as
3
an intermediate. Then, this amide, probably due to p-TsOH, cyclized and formed the salt of (1S,2S,4aS,8aS)-2,5,5,8a-
tetramethyldecahydro-1H-naphtho[1,2][5,6]-2-methyl-4,5-dihydro[1,3,6]oxazine with p-TsOH (19), treatment of which with
KOH solution (10%) in MeOH at 20°C or filtration of a solution of the salt in CH Cl through a column of Al O produced
2
2
2 3
1,3,6-oxazine 20, the structure of which was confirmed by elemental analysis and spectral data. Oxazine 20 was also
characterized by preparing its picrate and hydrochloride.
Reaction of 9 with PCl in Et O at 0°C produced a multi-component mixture of products, column chromatography of
5
2
which over silica gel isolated and identified pure crystalline norambreinolide (11) (32% yield). A mixture of compounds that
1
13
15
according to H, C, and N NMR spectra most likely contained 11-acetylaminodrimenes 18, 21, and 22 that are isomeric at
the double bond and 11-methylaminooxodrimenes 23 and 24 also eluted from the column.
15
Also, a mixture of compounds containing two N-containing compounds according to N NMR spectra eluted from
the column. One of these compounds was a 1,3,6-oxazine (20); another, apparently hydroxyamide 25 based on spectral data
(Scheme 2).
The observation of 18, 20, 21-24, and 11 among the products of the reaction of 9 with PCl can be explained by
5
assuming that the Beckmann rearrangement under these conditions occurred with both anti-migration of the bulkier radical to
form 7 and migration of the C methyl to form 25 as intermediates. Hydroxyamides 7 and 25 under the reaction conditions
13
underwent further conversion. Their dehydration resulted in the formation of 18 and 21-24. Loss of water and subsequent
cyclization produced 1,3,6-oxazine 20 from 7. Hydroxyamide 25 was hydrolyzed and converted into 26 that formed lactone
norambreinolide 11.
540

NHCOCH
CONHCH
3
NHCOCH
CONHCH
3
3
3
NOH
OH
PCl
5
+
+
OH
OH
Et O, 0°C
2
-H O
2
17%
9
23, 24
23:ꢁ7,8; 24:ꢁ8,12
7
25
18, 21, 22
H O
2
-H O
2
18: ꢁꢅ ꢆ; 21:ꢁ7,8; 22:ꢁ8,12
O
N
COOH
OH
CH
3
C
O
O
-H O
2
32%
20
26
11
Scheme 2
Unfortunately, not all products from reaction of 9 with PCl could be isolated pure and convincingly identified.
5
Thus, we synthesized new N-containing drimane sesquiterpenoids including those with 1,2,6- and 1,3,6-oxazine
rings.
EXPERIMENTAL
Melting points were determined on a Boetius heating stage. IR spectra were recorded on Perkin–Elmer Spectrum
13
100FT-IR or Specord 74 spectrophotometers. PMR and C NMR spectra were recorded in CDCl on a Bruker AC-E 400
3
(400 and 100 MHz) spectrometer. Chemical shifts are given on the ꢂ-scale in ppm relative to CHCl resonances as an internal
3
13
standard (resonances at ꢂ 7.24 and 77.00 ppm, respectively). Resonances in C NMR spectra were assigned using the DEPT
program and comparison with spectra of known related compounds [5, 6].
The course of reactions was monitored by TLC on Silufol plates with detection by I vapor. Column chromatography
2
used silica gel L 100/400 ꢃm. Ether extracts were dried over anhydrous MgSO .
4
Preparation of Oxime 9. A. Asolution of 11-dihomodriman-8ꢀ-ol-12-one (10, 1 g, 3.75 mmol) in EtOH (5 mL) and
Py (5 mL) was treated with NH OH4HCl (0.29 g, 4.17 mmol), stirred, left at 18–20°C for 24 h, and treated with H O (100 mL).
2
2
The resulting white oily solid crystallized upon standing. The precipitate was filtered off, washed with water, dried in air, and
recrystallized from hexane to afford crystals (0.99 g, 94%) with mp 117–118°C.
The product was a mixture of the Z- and E-isomers of 9 according to TLC and spectral data. TLC: benzene:ether
(1:2), R 0.33 and 0.56, C H NO .
f
17 31
2
–1
IR spectrum (KBr, ꢄ, cm ): 3500 (OH), 3340 (br.), 1660 (C=N), 1115, 940 (N–O).
PMR spectrum (ppm, J/Hz): (characteristic resonances) 0.79 (3H, s, CH -17), 0.80 (3H, s, CH -15), 0.87 (3H, s,
3
3
CH -16), 1.20 (3H, s, CH -14), 1.92 (3H, s, CH -13), 2.19 (1H, dd, J = 3.6, 15.6), 2.42 (1H, dd, J = 6.8, 16) [C (H )], 8.64
3
3
3
11
2
13
(br.s, OH). Resonances in the C NMR spectrum of one of the isomers, which was probably the energetically more favorable
E-isomer, were about twice as strong as those of the other.
13
C NMR spectrum (ppm): (major isomer of 9) 14.65 (C-17), 15.27 (C-13), 18.54 (C-2), 20.27 (C-6), 21.54 (C-15),
24.22 (C-14), 31.57 (C-11), 33.33 (C-4), 33.43 (C-16), 38.81 (C-10), 39.76 (C-1), 41.79 (C-3), 43.95 (C-7), 56.03 (C-5),
56.85 (C-9), 73.77 (C-8), 161.13 (C-12).
13
C NMR spectrum (ppm): (minor isomer of 9) 15.16 (C-17), 18.63 (C-2), 20.06 (C-6), 20.19 (C-13), 21.52 (C-15),
24.07 (C-11), 24.43 (C-14), 33.33 (C-4), 33.43 (C-16), 38.94 (C-10), 39.88 (C-1), 41.83 (C-3), 42.87 (C-7), 56.16 (C-5),
58.40 (C-9), 73.54 (C-8), 161.21 (C-12).
15
N NMR spectrum (ppm): 335.8 and 338.51 (=N–OH of Z- and E-isomers).
541

B. A solution of hydroxyketone 10 (100 mg, 0.37 mmol) in EtOH (0.5 mL) and Py (0.5 mL) was treated with
NH OH4HCl (42 mg, 0.60 mmol), heated at 95–105°C for 1 h, cooled, treated with water (10 mL) and HCl solution (5 mL,
2
5%), and extracted with ether (3 ꢇ 10 mL). The extracts were washed with HCl (5%, 3 ꢇ 3 mL), NaHCO solution (3 ꢇ 3 mL),
3
and water (3 ꢇ 3 mL) and dried. The ether was distilled off. The solid was recrystallized from hexane to afford a mixture of
the Z- and E-isomers of 9 (89 mg, 84%) with mp 118–119°C.
Products from Reaction of 9 with Ac O in Py. A solution of 9 (100 mg, 0.35 mmol) in Py (0.5 mL) and Ac O
2
2
(0.17 mL, 184 mg, 1.80 mmol) was heated at 105–115°C for 1 h, cooled in an ice bath, treated with several pieces of ice and
dropwise with H SO (5 mL, 10%), and extracted with ether (3 ꢇ 10 mL). The extracts were washed with NaHCO solution
2
4
3
(3 ꢇ 3 mL) and water (3 ꢇ 3 mL) and dried. The ether was distilled off. The solid was chromatographed over a column of silica
gel (3.4 g) with elution by hexane:ether (9:1) to afford dehydrated oxime acetate (5 mg, 5%) as a mixture of isomers 13–15 in
a 50:39:11 ratio [PMR spectra had characteristic resonances (ppm) at 1.26 (s, CH –C=C), 1.89, 1.90, and 1.93 (3s,
3
3 CH –C=N–), 2.15, 2.17, and 2.19 (3s, 3 OAc), 4.72 and 4.82 (both 1H s, >C=CH ), 5.43-5.44 (m, >C=CH)]. The amounts
3
2
of 13–15 were determined in two ways. The amounts of 13 and 14 and their sum were determined by integrating the resonances
of OAc and (>C=CH) and (>C=CH ) groups for the three isomers. The content of the isomer with the tetrasubstituted double
2
bond (15) was determined by difference.
–1
IR spectrum (film, ꢄ, cm ): 3100 (>C=CH ), 1750 (OAc), 1640 (C=N), 1200, 930 (N–O), 880, 830 (>C=CH).
2
Elution by hexane:ether (2:3) afforded a mixture (104 mg, 90%) of the Z- and E-isomers of 12. TLC: benzene:ether
(1:2), R 0.31 and 0.48, C H NO .
f
19 33
3
–1
IR spectrum (film, ꢄ, cm ): 940 (N–O), 1200, 1750 (OAc), 1640 (C=N), 1115, 3470 (OH).
N NMR spectrum (ppm): 347.33 and 349.92 (2 ꢇ =N–OAc of the Z- and E-isomers). The ratio of the Z- and
15
E-isomers in the mixture was 1:4.9 (PMR spectrum). This ratio was determined by integrating resonances of methyls with
characteristic resonances (ppm) at 1.24 and 1.26 (2 CH –C–OH), 2.00 and 2.10 (2 CH –C=N), 2.14 and 2.18 (2 OAc). The
3
3
product was partially crystalline. Crystals were filtered off and washed with hexane to afford the Z-isomer of 12 (7 mg),
R 0.31, mp 105–107°C.
f
–1
IR spectrum (KBr, ꢄ, cm ): 3450 (OH), 1750 (OAc), 1640 (C=N), 1210, 1180, 980 (N–O).
PMR spectrum (ppm, J/Hz): 0.79 (3H, s, CH -17), 0.86 (3H, s, CH -16), 0.89 (3H, s, CH -15), 1.24 (3H, s, CH -14),
3
3
3
3
2.10 (3H, s, CH -13), 2.18 (3H, s, CH -19), 2.48 (1H, dd, J = 4.8, 14), 2.57 [1H, dd, J = 7.6, 14, C (H )].
3
3
11
2
13
C NMR spectrum (ppm): 15.16 (C-17), 18.54 (C-2), 19.86 (C-19), 20.31 (C-6), 20.41 (C-13), 21.56 (C-15), 24.09
(C-14), 26.26 (C-11), 33.36 (C-4), 33.48 (C-16), 39.04 (C-10), 39.63 (C-1), 41.71 (C-3), 44.55 (C-7), 56.22 (C-5), 58.11
(C-9), 73.58 (C-8), 168.79 (C-12), 169.42 (C-18).
15
N NMR spectrum (ppm): 347.41 (=N–OAc).
The E-isomer of 12 was a viscous liquid.
PMR spectrum (ppm, J/Hz): 0.80 (3H, s, CH -17), 0.84 (3H, s, CH -16), 0.88 (3H, s, CH -15), 1.26 (3H, s, CH -14),
3
3
3
3
2.00 (3H, s, CH -13), 2.14 (3H, s, CH -19), 2.35 (1H, dd, J = 4.4, 14.8), 2.58 [1H, dd, J = 8.0, 15.2, C (H )].
3
3
11
2
13
C NMR spectrum (ppm): 15.32 (C-17), 15.99 (C-13), 18.60 (C-2), 19.68 (C-19), 20.26 (C-6), 21.54 (C-15), 23.97
(C-14), 31.78 (C-11), 33.33 (C-4), 33.46 (C-16), 38.80 (C-10), 39.94 (C-1), 41.71 (C-3), 44.16 (C-7), 56.07 (C-5), 57.01
(C-9), 73.68 (C-8), 168.90 (C-12), 170.88 (C-18).
Preparation of (1S,2S,4aS,8aS)-2,5,5,8a-Tetramethyldecahydro-1H-naphtho[1,2][5,6]-3-methyl-4,5-
dihydro[1,2,6]oxazine (16). Oxime 9 (100 mg, 0.35 mmol) was treated with H PO (86%, 1 mL), heated at 60–70°C for 15
3
4
min until the oxime dissolved completely, heated at the same temperature for another hour, cooled in an ice bath, and treated
dropwise with water (20 mL). The white crystalline precipitate was filtered off, washed with water, dried in air, and recrystallized
from hexane to afford crystals (77 mg, 82%), mp 146–147°C. Elemental analysis and spectral data indicated that the product
was 1,2,6-oxazine 16, C H NO.
17 29
–1
IR spectrum (KBr, ꢄ, cm ): 1630 (C=N), 920 (N–O).
PMR spectrum (ppm): 0.79 (3H, s, CH -17), 0.82 (3H, s, CH -15), 0.88 (3H, s, CH -16), 1.11 (3H, s, CH -14), 1.92
3
3
3
3
(3H, s, CH -13).
3
13
C NMR spectrum (ppm): 14.36 (C-17), 18.33 (C-2), 19.42 (C-6), 19.67 (C-14), 21.48 (C-15), 22.00 (C-13), 23.29
(C-11), 33.14 (C-4), 33.27 (C-16), 35.93 (C-10), 38.65 (C-7), 38.90 (C-1), 41.81 (C-3), 49.29 (C-9), 56.06 (C-5), 75.28 (C-8),
155.11 (C-12).
15
N NMR spectrum (ppm): 349.96 (=N–O).
542

Products from Reaction of 9 with p-TsCl in Py. A solution of 9 (200 mg, 0.71 mmol) in Py (2 mL) was treated with
p-TsCl (164 mg, 0.86 mmol), stirred, left at 20°C for 30 min, treated dropwise with HCl (16 mL, 5%), cooled in an ice bath,
and extracted with ether (3 ꢇ 10 mL). The extracts were washed with HCl (5%, 3 ꢇ 3 mL), NaHCO solution (3 ꢇ 3 mL), and
3
water (3 ꢇ 3 mL) and dried. The ether was distilled off. The solid (280 mg, 90%) was partially crystalline. Crystals were
flitered off and washed with hexane:ether (99:1) to afford the product (20 mg), mp 61–62°C, that was oxime tosylate 17,
C H SNO , according to spectral data and elemental analysis.
24 37
4
–1
IR spectrum (KBr, ꢄ, cm ):3580 (OH),3350, 3270, 1670 (C=N), 1640, 1600 (benzene ring), 1450, 1350 (O–SO –),
2
1280, 1180, 1170, 1080, 1030, 930 (N–O), 870, 780.
PMR spectrum (ppm, J/Hz): 0.75 (3H, s, CH -17), 0.80 (3H, s, CH -15), 0.85 (3H, s, CH -16), 1.07 (3H, s, CH -14),
3
3
3
3
1
1
1.98 (3H, s, CH -13), 2.22–2.38 (2H, m, H -11), 2.42 (3H, s, CH -C H ), 7.30 (2H) and 7.83 (2H, J = 8.8, AA BB -system,
3
2
3
6 4
C H ).
6
4
The filtrate from the separated crystals of tosylate oxime 17 was evaporated. The solid (260 mg) was dissolved in
CH CN (3 mL) and refluxed for 30 min. The CH CN was distilled off. The crystalline solid was washed with a small amount
3
3
of ether to afford a crystalline product (240 mg), mp 138–139°C, that was the salt of a 1,3,6-oxazine with p-TsOH (19)
according to IR and PMR spectral data.
–1
IR spectrum (KBr, ꢄ, cm ): 3250 (NH), 3130, 1730 (=CH ), 1680, 1530, 1450, 1220, 1120, 1030, 1000, 805, 680,
2
(p-TsOH).
PMR spectrum (ppm, J/Hz): 0.78 (3H, s, CH -15), 0.82 (3H, s, CH -13), 0.86 (3H, s, CH -14), 1.38 (3H, s, CH -12),
3
3
3
3
2.32 (3H, s, CH -17), 2.38 (3H, s, CH -C H ), 3.02-3.57 (2H, m, H -11), 7.15 and 7.79 (2H, J = 8.06, 8.20, AA1BB1-system,
3
3
6
4
2
C H ), 13.09 (1H, br.s, SO H).
6
4
3
Preparation of (1S,2S,4aS,8aS)-2,5,5,8a-Tetramethyldecahydro-1H-naphtho[1,2][5,6]-2-methyl-4,5-
dihydro[1,3,6]oxazine with p-TsOH (20). A. p-Toluenesulfonate 19 (220 mg) was treated with KOH solution (4.4 mL, 10%)
in MeOH and stirred at 20°C for 1 h. The MeOH was vacuum distilled. The solid was treated with water (20 mL) and
extracted with ether (5 ꢇ 10 mL). The extract was washed with water (3 ꢇ 5 mL) and dried. The ether was distilled off to afford
a viscous liquid (127 mg, 95%) of 20, the structure of which was confirmed by elemental analysis and spectral data, C H NO.
17 29
–1
IR spectrum (CCl , ꢄ, cm ): 1674 (C=N).
4
PMR spectrum (ppm, J/Hz): 0.81 (3H, s, CH -15), 0.83 (3H, s, CH -13), 0.88 (3H, s, CH -14), 1.24 (3H, s, CH -12),
3
3
3
3
1.85 (3H, s, CH -17), 3.13 (1H, ddd, J = 1.6, 12.4, 16), 3.29 (1H, dd, J = 4.8, 16) [C (H )].
3
11
2
13
C NMR spectrum (ppm): 15.37 (C-15), 18.38 (C-2), 19.59 (C-6), 21.45 (C-13), 21.68 (C-17), 22.08 (C-12), 33.15
(C-4), 33.34 (C-14), 36.12 (C-10), 38.99 (C-1), 40.37 (C-7), 40.76 (C-3), 41.83 (C-11), 52.05 (C-5), 56.28 (C-9), 76.72 (C-8),
156.85 (C-16).
15
N NMR spectrum (ppm): 212.3 (–N=C–O).
B. Asolution of p-toluenesulfonate 19 (20 mg) in CH Cl (1 mL) was filtered through a column ofAl O (Brockmann
2
2
2 3
activity II, 0.4 g). The column was eluted with CH Cl (2 mL) to afford 1,3,6-oxazine 20 (7 mg, 58%).
2
2
Preparation of 1,3,6-Oxazine 20 Picrate. A solution of 1,3,6-oxazine 20 (16 mg) in EtOH was treated with an
aqueous solution of picric acid. The resulting yellow precipitate was filtered off, washed with water, dried in air, and recrystallized
from EtOH to afford the picrate of 20 (10 mg), mp 150–151°C, C H NO4C H N O 41/2C H OH.
17 29
6
3
3
7
2 5
–1
IR spectrum (KBr, ꢄ, cm ): 1670 (C=N), 1630 (picric acid), 1600, 1520, 1420, 1340, 1300, 1270, 1070, 900, 730,
700.
Preparation of 1,3,6-Oxazine 20 Hydrochloride. A solution of 1,3,6-oxazine 20 (40 mg) in hexane (1 mL) was
treated with a saturated ether solution of HCl until acidic. Solvents were evaporated to afford crystals (46 mg) of 20
hydrochloride, mp 156–157°C.
–1
IR spectrum (KBr, ꢄ, cm ): 2620 (C=NH), 1650.
Products from Reaction of 9 with PCl in Ether. A stirred suspension of PCl (1.1 g, 5.28 mmol) in anhydrous
5
5
ether (5 mL) was treated dropwise over 5 min with a solution of 9 (0.5 g, 1.78 mmol) in anhydrous ether (22 mL) with
cooling in an ice bath, stirred at the same temperature for 30 min, treated with several pieces of ice, and extracted with ether
(3 ꢇ 10 mL) (extract I). The extract was washed with water (3 ꢇ 5 mL) and dried. The ether was distilled off. The aqueous
extracts were combined with the acidic aqueous layer, made basic with NH OH (24%, 15 mL), and extracted with ether
4
(3 ꢇ 20 mL) (extract II). The extract was washed with water (3 ꢇ 5 mL) and dried. The ether was distilled off. The solid
(0.4 g) after distillation of ether from extract I was dissolved in CHCl (2 mL) and chromatographed over a column of silica gel
3
543

(12 g) with elution by CHCl to afford a crystalline product (90 mg, 20%), mp 123–124°C, that corresponded to norambreinolide
3
13
11 according to mp and IR, PMR, and C NMR spectral data [5]; lit. mp 123–124°C [7].
–1
IR spectrum (KBr, ꢄ, cm ): 1772 (lactone).
PMR spectrum (ppm, J/Hz): 0.84 (3H, s, CH -16), 0.89 (3H, s, CH -14), 0.91 (3H, s, CH -15), 1.34 (3H, s, CH -13),
3
3
3
3
2.23 (1H, dd, J = 6.4, 16), 2.39 (1H, dd, J = 14.8, 16.4) [C (H )].
11
2
13
C NMR spectrum (ppm): 15.03 (C-16), 18.05 (C-2), 20.52 (C-6), 20.88 (C-13), 21.53 (C-14), 28.68 (C-11), 33.08
(C-4), 33.13 (C-15), 36.01 (C-10), 38.67 (C-1), 39.46 (C-7), 42.13 (C-3), 56.61 (C-5), 59.08 (C-9), 86.35 (C-8), 176.85
(C-12).
Amixture of CHCl :CH OH (99:1) eluted a viscous liquid (76 mg, 17%) that was a mixture of 11-acetylaminodrimenes
3
3
(18, 21, 22) isomeric at the double bond and 11-methylaminooxodrimenes 23 and 24.
–1
IR spectrum (CCl , ꢄ, cm ): 3291 (NHCO), 3087, 1645, 1552, 1412 (=CH ), 1280, 887, 845 (>C=CH), 813.
4
2
PMR spectrum (ppm, J/Hz): (characteristic resonances) 1.62, 1.68, 1.69 (3s, 3 CH on double bond), 1.93, 1.95, 1.96
3
(3s, 3 COCH ), 2.78 (d, J = 4.8) and 2.82 (d, J = 5.2) (2 NHCH ), 4.50 and 4.53 (both 1H s, >C=CH of the first isomer),
3
3
2
4.79 and 4.91 (both 1H s, >C=CH of the second isomer), 5.11, 5.38, 5.42, 5.50, 5.53 (5 br.s, 5 NH), 5.54 and 5.55 (2 br.s,
2
2 ꢇ >C=CH).
13
C NMR spectrum (ppm): (characteristic resonances) 172.22, 173.59, 174.37 (3 NHCOCH ), 169.61 and 169.93 (2
3
CONHCH ), 122.60 and 124.94 (2 ꢇ >C=CH), 106.52 and 106.93 (2 ꢇ >C=CH ). The total number of resonances in the
3
2
spectra corresponded to the presence of five isomers with 17 C atoms in each in the mixture.
15
N NMR spectrum (ppm): 100.95, 101.60, 118.09, 120.73, 123.39 (5 NHCO).
The solid (0.1 g) after distillation of ether from extract II was dissolved in hexane (3 mL) and chromatographed over
a column of silica gel (3 g) with elution by CHCl to afford a crystalline product (50 mg), mp 123–124°C, that was identical
3
by TLC and spectral data to norambreinolide 11. The overall yield of 11 was 140 mg (32%). A mixture of CHCl :CH OH
3
3
15
(99:1) eluted a product (40 mg) that contained two N-containing compounds according to N NMR. One of the components
1
13
15
of this mixture was 1,3,6-oxazine 20 according to H, C, and N NMR spectral data, which are given above. The second
was most probably hydroxyamide 25. However, these compounds could not be separated pure from the mixture and convincingly
identified.
15
N NMR spectrum (ppm): 211.02 (–N=C–O), 102.05 (NHCH ).
3
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1.
2.
3.
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