Total synthesis and structural elucidation of (-)-maurenone

Article abstract of DOI:10.1021/jo051753c

The total synthesis of (2S,3S)-2,3-dihydro-6-[(1′S, 2′R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1″,S)-1-methylpropyl] -4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was achieved in nine linear steps (13% overall yield)

Full text of DOI:10.1021/jo051753c

Total Synthesis and Structural Elucidation of (-)-Maurenone
Julia S. Crossman and Michael V. Perkins*
School of Chemistry, Physics, and Earth Sciences, Flinders UniVersity, GPO Box 2100,
Adelaide, South Australia 5001, Australia
mike.perkins@flinders.edu.au
ReceiVed August 19, 2005
The total synthesis of (2S,3S)-2,3-dihydro-6-[(1′S, 2′R)-2-hydroxy-1-methylbutyl]-3,5-dimethyl-2-[(1′′S)-
1-methylpropyl]-4H-pyran-4-one (3), the (-)enantiomer of the marine polypropionate, maurenone, was
achieved in nine linear steps (13% overall yield) from (R)-2-benzylpentan-3-one ((R)-14) and (R)-2-
benzoyloxypentan-3-one ((R)-15). Key fragments were synthesized using highly diastereoselective syn
and anti boron aldol reactions and were coupled using a lithium-mediated aldol reaction. Trifluoroacetic
acid-promoted cyclization/dehydration was then used to install the γ-dihydropyrone ring. Eight isomers
of one enantiomeric series were synthesized by coupling two ketones with each of four aldehydes.
Comparison of the 13C NMR data for the eight isomers with that reported for maurenone established the
relative stereochemistry of the natural product.
Introduction
of cases, the stereochemistry of these natural products has been
established by stereocontrolled synthesis of putative structures.8
Maurenone was isolated in 1986 by Faulkner and co-workers
from specimens of the pulmonate mollusc Siphonaria maura,
collected from Jaco Beach, Costa Rica.9 The structure of
maurenone was assigned, on the basis of 1H and 13C NMR data,
to contain the relatively uncommon, tetra-substituted dihydro-
pyrone moiety. The planar structure was determined, as shown
in Figure 1, but the stereochemical information was limited and
the configurations at C3, C4, and C10 were not assigned. Only
an anti relationship between the C8 and C9 substituents was
indicated by the large coupling constant J8,9 ) 12.3 Hz.
Thus, considering the anti relationship between C8 and C9,
there are 16 possible stereoisomers (8 pairs of enantiomers), 1
of which corresponds to maurenone. We set out to synthesize
Marine pulmonates of the genus Siphonaria are a rich source
of diverse polyketide-derived natural products.1 Examples
containing oxygen heterocycles include siphonarin A and B2
(spiroacetal and pyrone), muamvatin3 (trioxaadamantane) den-
ticulatin A and B4 (hemiacetal), membrenone A-C (dihyropy-
rone),5 and vallartanones A and B (dihydropyrone and pyrone).6
Nearly all species examined have contained metabolites of
polypropionate origin that appear to share a common biosyn-
thesis with macrolide and polyether antibiotics.7 In a number
(1) Davies-Colman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15, 477.
(2) Hochlowski, J.; Coll, J.; Faulkner, D. J.; Biskupiak, J. E.; Ireland,
C. M.; Zheng, Q.; He, C.; Clardy, J. J. Am. Chem. Soc. 1984, 106, 6748.
(3) Roll, D. M.; Biskupiak, J. E.; Mayne, C. L.; Ireland, C. M. J. Am.
Chem. Soc. 1986, 108, 6680.
(4) Hochlowski, J. E.; Faulkner, D. J.; Matsumoto, G. K.; Clardy, J. J.
Am. Chem. Soc. 1983, 105, 74.
(5) Ciavatta, M. L.; Trivellone, E.; Villani, G.; Cimino, G. Tetrahedron
Lett. 1993, 34, 6791.
(6) Manker, D. C.; Faulkner, D. J. J. Org. Chem. 1989, 54, 5374.
(7) (a) Garson, M. J.; Goodman, J. M.; Paterson, I. Tetrahedron Lett.
1994, 35, 6929. (b) Garson, M. J. Chem. ReV. 1993, 93, 1699. (c) Manker,
D. C.; Garson, M. J.; Faulkner, D. J. J. Chem. Soc., Chem. Commun. 1988,
1061. (d) Garson, M. J.; Jones, D. D.; Small, C. J.; Liang, J.; Clardy, J.
Tetrahedron Lett. 1994, 35, 6921.
(8) (a) Arimoto, H.; Yokoyama, R.; Nakamura, K.; Okumura, Y.;
Uemura, D. Tetrahedron 1996, 52, 13901. (b) Arimoto, H.; Yokoyama,
R.; Okumura, Y. Tetrahedron Lett. 1996, 37, 4749. (c) Perkins, M. V.;
Sampson, R. A. Tetrahedron Lett. 1998, 39, 8367. (d) Perkins, M. V.;
Sampson, R. A. Org. Lett. 2001, 3, 123. (e) Sampson, R. A.; Perkins, M.
V. Org. Lett. 2002, 4, 1655. (f) Lister, T.; Perkins, M. V. Aust. J. Chem.
2004, 57, 787.
(9) Manker, D. C.; Faulkner, D. J.; Xe, C. F.; Clardy, J. J. Org. Chem.
1986, 51, 814.
10.1021/jo051753c CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/13/2005
J. Org. Chem. 2006, 71, 117-124
117

Crossman and Perkins
SCHEME 1. Retrosynthetic Analysis of Maurenone
FIGURE 1. Structure of maurenone reported by Faulkner and co-
workers.9
aldehydes 16 and 17 are available from an aldol reaction
between benzyloxy-protected ketones (S)-15 and (R)-15 and
propanal (22) after hydrolysis and oxidative cleavage. Notably,
the protecting group on the ketone dictates the enolate geom-
etry,11 and benzyl-protected ketones (R)-14 and (S)-14 can be
used to prepare an enantiomeric pair of syn aldehydes 18 and
19. Ketones 20 and 21 can be prepared by a similar anti selective
aldol reaction between (R)-15 and (S)-15 and (S)-2-methylbu-
tanal (23).
FIGURE 2. Possible isomers of maurenone (10S enantiomeric series).
The synthesis of anti-anti ketone 20 (Scheme 3) began with
an asymmetric aldol reaction between the dicyclohexylboron
enolate of R-chiral ketone (R)-1511 and R-chiral aldehyde 23
(obtained by Swern oxidation12 of (S)-2-methylbutan-1-ol). The
facial preference of the ketone controls the formation of C8
and C9 stereocenters in a mismatched double stereodifferenti-
ating13 anti aldol reaction to give compound 24 (83% yield,
90% ds). Silyl protection (TESOTf, 2,6-lutidine)14 followed by
controlled samarium diiodide (2-3 eqiv of SmI2) mediated
cleavage of benzoate ester 2511 gave ethyl ketone 20 in good
yield (93%, 75% over three steps).
The alternative anti-syn ketone isomer 21 was synthesized
via compounds 26 and 27 (73%, over three steps) using the
same sequence as that described in Scheme 3, starting from
(S)-2-benzoyloxypentan-3-one ((S)-15) (Scheme 4). In this case,
the double stereodifferentiating reaction of R-chiral ketone (S)-
15 was matched with the Felkin13 preference of chiral aldehyde
23, giving aldol product 26 with no detectable minor isomer
(83% yield, >95% ds).
The synthesis of anti aldehyde 16 (Scheme 5) began with a
similar substrate-controlled anti aldol coupling between the
dicyclohexylboron enolate of R-chiral ketone (S)-1511 and
propanal (22). In this case, the stereoselectivity with the achiral
aldehyde is very high, giving aldol product 28 with no observed
minor isomer. The generated alcohol was then protected as TBS
ether 29,15 and the reduction of both ketone and ester function-
alities with LiBH4 gave 1,2-diol 30. Oxidative cleavage using
all eight possible isomers of one enantiomeric series to determine
the stereochemistry of the natural product.10 The series of
compounds 1-8 (Figure 2) containing the S configuration at
C10 was chosen because of the commercial availability of (S)-
2-methylbutan-1-ol starting material.
Results and Discussion
We wished to employ a common strategy that could be used
to generate the eight isomers using a number of common
intermediates and a minimum number of steps. Scheme 1
outlines our retrosynthetic strategy for the maurenone structure
with all required configurations at C3, C4, C8, and C9.
Dihydropyrone 9 can be envisaged to arise by acid-catalyzed
dehydration and deprotection of the corresponding hemiacetal
10. Formation of hemiacetal 10 was proposed to occur by
selective deprotection and cyclization of dione 11. Dione 11
has pseudosymmetry but was preferentially prepared by an aldol/
oxidation disconnection between C5 and C6 using aldehyde 12
and ketone 13. Using this strategy, the eight isomers 1-8 of
compound 9 can be prepared from four isomers of aldehyde 12
and two isomers of ketone 13.
Our approach to the formation of required aldehydes 16-19
and ketones 20 and 21 is shown in Scheme 2. We proposed to
exploit the high π-facial selectivity11 in syn and anti aldol
couplings of lactate-derived R-chiral ketones 14 and 15 to
generate all of the required stereocenters. Enantiomeric anti
(10) For recent synthetic work on other siphonariid-derived compounds,
see (a) Debrabander, J.; Oppolzer, W. Tetrahedron 1997, 53, 9169. (b)
Yamamura, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1997, 70, 2025. (c)
Hoffmann, R. W.; Dahmann, G. Liebigs Ann. Chem. 1994, 837. (d)
Andersen, M. W.; Hildebrandt, B.; Dahmann, G.; Hoffmann, R. W. Chem.
Ber. 1991, 124, 2127. (e) Paterson, I.; Chen, D. Y.-K.; Franklin, A. S. Org.
Lett. 2002, 4, 391. (f) Paterson, I.; Chen, D. Y. K.; Acena, J. L.; Franklin,
A. S. Org. Lett. 2000, 2, 1513. (g) Paterson, I.; Perkins, M. V. Tetrahedron
1996, 52, 1811. (h) Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993,
115, 1608. (i) Paterson, I.; Perkins, M. V. Tetrahedron Lett. 1992, 33, 801.
(j) Marshall, J. A.; Ellis, K. C. Org. Lett. 2003, 5, 1729.
(11) (a) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35, 9087.
(b) Paterson, I.; Wallace, D. J.; Velazquez, S. M. Tetrahedron Lett. 1994,
35, 9083. (c) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35, 9477.
(d) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
(12) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(13) Roush, W. R. J. Org. Chem. 1991, 56, 4151.
(14) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher,
U. J. Org. Chem. 1985, 50, 2095.
(15) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
118 J. Org. Chem., Vol. 71, No. 1, 2006

Structural Elucidation of (-)-Maurenone
SCHEME 2. Proposed Synthesis of Aldehyde and Ketone Fragments
SCHEME 3. Synthesis of anti-anti Ketone
SCHEME 5. Synthesis of anti Aldehydes
SCHEME 4. Synthesis of anti-syn Ketone
SCHEME 6. Synthesis of syn Aldehydes
periodate11 gave anti aldehyde 16 in good yield (79% over four
steps). Synthesis of enantiomeric aldehyde 17 was performed
in an identical manner, starting from (R)-benzoyloxypentan-3-
one ((R)-15) (55% over four steps).
The synthesis of aldehyde 18 (Scheme 6) began with a
substrate-controlled aldol coupling between the dicyclohexyl-
boron enolate of R-chiral ketone (R)-1411 and propanal (22),
giving syn aldol product 31. Notably, the change in the pro-
tecting group from Bz (in 15) to Bn (in 14) and the use of modi-
fied enolization conditions generates the cis enolate and thus
syn aldol product 31. Oxidative cleavage of this benzyl protected
compound to the aldehyde requires a modified sequence. The
hydroxyl was protected as TBS ether15 32, and carbonyl reduc-
tion gave compound 33. Hydrogenolysis of benzyl ether 33 gave
1,2-diol 34, which was subsequently oxidized with NaIO4 11 to
aldehyde 18 (85%, 49% over five steps). Synthesis of enantio-
meric aldehyde 19 was performed in an identical manner, start-
ing from (S)-benzylpentan-3-one ((S)-14) (74% over five steps).
The synthesis of all eight possible isomers of maurenone was
now possible through the coupling of each of the two ketone
isomers (20 and 21) with the four aldehyde isomers (16-19).
Attempts to couple the titanium(IV) enolate (TiCl4, i-Pr2EtN)16
of ketone 20 with aldehyde 18 proved troublesome because of
the desilylation of the ketone during enolization. Fortunately,
higher yields were achieved by employing a lithium enolate.
The treatment of ketone 20 with lithium bis(trimethylsilyl)-
amide17 (Scheme 7) at -78 °C and the subsequent addition of
(16) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem.
Soc. 1995, 117, 9073.
J. Org. Chem, Vol. 71, No. 1, 2006 119

Crossman and Perkins
SCHEME 7. Lithium-Mediated Aldol Coupling/Acid
Promoted Cyclization-Dehydration
FIGURE 3. Difference in chemical shift (δ∆) for isomers 5-8 derived
from ketone 21.
aldehyde 18 at -78 °C, which was stirred for 2 h, gave coupled
product 35 in moderate yield with a moderate level of diaste-
reoselectivity (74% ds). In this and other cases, the isomers
could be separated and characterized. Ultimately, however, the
stereochemistry at C5 and C6 was of little significance because
they are both lost in subsequent steps. Thus, aldol adduct 35
was oxidized to corresponding dione 36 under Swern condi-
tions.12 Selective cleavage of triethylsilyl ether was achieved
with trifluoroacetic acid, which also promoted spontaneous
cyclization and dehydration to dihydropyrone 37. Finally,
liberation of the C3 alcohol with buffered HF-pyridine18 gave
desired product 3 in good yield (90%, 25% over four steps).
Using this approach, synthesis of each of the possible isomers
of maureone in the 10S enantiomeric series was accomplished
using the same sequence as that described in Scheme 7.
Stereochemical assignment of the natural product was carried
out by comparison of NMR spectra reported for the natural
product with those obtained for various isomers 1-8. There
was little difference found in the 1H spectrum from one isomer
to the next, so our attention was turned to the 13C NMR spectra.
An inconsistency was immediately noted in that C7 for the
natural product was reported9 at δ ) 208.2 ppm, whereas for
all isomers 1-8, C7 was found to be in the range of δ ) 195.5-
195.7 ppm. The chemical shift of δ ) ∼195 ppm is consistent
with previous findings for the presence of the γ-dihydropyrone
carbonyl.8 We thus assumed that the signal at 208.2 was
misreported in the isolation paper.19 In addition, only 15 of the
required 16 carbon signals were reported,9 and the signal for
the quaternary C6 at δ ) ∼109 ppm was missing.
FIGURE 4. Difference in chemical shift (δ∆) for isomers 1-4 derived
from ketone 20.
in the chemical shifts of a number of peaks for all four
compounds, most notably at C9, C11, and C16. For these three
carbons, the ∆δ is 2.3-4.8 ppm for compounds 5-8. On this
basis, these structures were ruled out for the natural product
maurenone.
A comparison with the compounds derived from ketone 20,
however, shows a much closer correlation with the natural
product maurenone (Figure 2) with a maximum ∆δ of 1.7 ppm.
In this series, isomer 1 shows the largest differences for C1
(∆δ ) 1.7 ppm) and C12 (∆δ ) -1.7 ppm), and isomer 2
shows a large difference for C13 (∆δ ) 1.7 ppm) along with a
number of other more minor deviations. On this basis, isomers
1 and 2 can be excluded, leaving the two syn aldehyde-derived
isomers 3 and 4. Small but consistent differences in the chemical
shifts for isomer 4 are observed in a range of peaks. Isomer 3
alone shows an almost perfect correlation (∆δ e (0.1 ppm)
with all of the peaks reported for maurenone,9 and on this basis,
the relative configuration of the natural product maurenone is
assigned as shown for isomer 3.
Despite these inconsistencies, the differences in the 13C NMR
spectra were highlighted in Figures 3 and 4 by plotting the
difference in chemical shift for each of the carbons20 of isomers
1-8 compared to that reported in the original isolation. Figure
3 shows the comparison of the chemical shifts of compounds
5-8 derived from ketone 21. There is a significant difference
(17) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.;
Scheidt, K. A. J. Org. Chem. 2002, 67, 4275.
(18) Robins, M. J.; Samano, V.; Johnson, M. D. J. Org. Chem. 1990,
55, 410.
(19) Attempts to obtain copies of the original spectra were unsuccessful;
thus, no direct comparison with the original spectra was possible.
(20) The signals due to C6 and C7 were excluded from this comparison
because of their absence from and apparent misreporting, respectively in
the isolation report (ref 9).
1
The H and 13C NMR data reported for the natural product
and those obtained for isomer 3 are reported in Table 1 and
show an excellent correlation. The mass spectral, IR, and UV
data for isomer 3 were also consistent with those reported for
120 J. Org. Chem., Vol. 71, No. 1, 2006

Structural Elucidation of (-)-Maurenone
1
TABLE 1. Comparison of the H and 13C NMR Data for
m, ArH), 7.49-7.44 (2H, m, ArH), 5.46 (1H, q, J ) 7.2 Hz,
BzOCH), 3.60-3.53 (1H, m, CHOH), 3.08 (1H, apt qn, J ) 6.9
Hz, C(dO)CH(CH3)), 2.39 (1H, d, J ) 7.2 Hz, OH), 1.62-1.48
(1H, m, CH(CH3)CH2), 1.57 (3H, d, J ) 7.2 Hz, BzOCH(CH3)),
1.27 (3H, d, J ) 6.9 Hz, C(dO)CH(CH3)), 1.31-1.13 (2H, m,
CH2CH3), 0.93 (3H, d, J ) 6.6 Hz, CH(CH3)CH2), 0.90 (3H, t, J
) 7.1 Hz, CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 212.4, 133.4,
129.8, 129.5, 128.5, 78.2, 77.2, 74.7, 44.8, 37.1, 22.7, 16.3, 16.0,
14.8, 11.6; IR (film, cm-1) 2967, 2936, 2876, 1718, 1453, 1316,
Maurenone and Isomer 3 (the Structure Matching the Natural
Product)
maurenonea
δH, m, 3J[Hz]c
isomer 3b
δH, m, 3J[Hz]c
1268, 1118, 1006, 713, 667; [R]20 -43.1 (c 1.1, CHCl3); HRMS
D
carbon
no.
(ESI) found 293.1747, C17H23O3H+ requires 293.1747; LREIMS
292 (1%), 235 (5%), 150 (25%), 113 (8%), 105 (100%), 97 (19%),
77 (34%), 57 (28%), 51 (12%).
δCc
δCc
1
2
0.95, t, 7.4
1.40, m
10.3
28.0
0.96, t, 7.2
1.49 and 1.39, m
10.2
27.9
(2R,4S,5S,6S)-2-Benzoyloxy-5-triethylsilyloxy-4,6-dimethyloc-
tan-3-one (25). To a solution of alcohol 24 (0.42 g, 1.45 mmol) in
CH2Cl2 (14.5 mL) at -78 °C was added 2,6-lutidine (0.67 g, 5.78
mmol) dropwise, followed immediately by TESOTf (0.98 mL, 4.35
mmol). The resulting solution was stirred at -78 °C for 1 h before
quenching with NaHCO3 (sat. aq, 30 mL). The product was
partitioned onto H2O (30 mL), extracted with CH2Cl2 (3 × 30 mL),
dried (MgSO4), and concentrated in vacuo. The product was purified
by column chromatography (50% mixed hexanes/CH2Cl2, Rf )
0.40), yielding 0.57 g (97%) of 25 as a clear, colorless oil. 1H NMR
(300 MHz, CDCl3) δ 8.10-8.06 (2H, m, ArH), 7.59-7.53 (1H,
m, ArH), 7.46-7.41 (2H, m, ArH), 5.44 (1H, q, J ) 6.9 Hz,
CH(CH3)OBz), 3.94 (1H, dd, J ) 9.0, 2.1 Hz, CHOTES), 3.11
(1H, dq, J ) 9.0, 6.9 Hz, (CdO)CH(CH3)), 1.57-1.39 (1H, m,
CH(OTES)CH(CH3)), 1.51 (3H, d, J ) 6.9 Hz, BzOCH(CH3)),
1.23-1.12 (2H, m, CH2CH3), 1.09 (3H, d, J ) 6.9 Hz, (CdO)-
CH(CH3)), 0.95 (3H, d, J ) 6.9 Hz; CH(CH3)CH2CH3), 0.92 (9H,
t, J ) 7.9 Hz, Si(CH2CH3)3), 0.89 (3H, t, J ) 7.2 Hz, CH2CH3),
0.56 (6H, q, J ) 7.2 Hz, Si(CH2CH3)3); 13C NMR (75.5 MHz,
CDCl3) δ 209.2, 165.6, 133.1, 129.7, 128.3, 78.1, 75.0, 45.9, 38.9,
23.8, 15.6, 15.4, 14.2, 12.5, 6.9, 5.2; IR (film, cm-1) 2962, 2914,
2878, 1724, 1454, 1382, 1316, 1301, 1268, 1177, 1116, 1059, 1027,
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3.65, ddd, 7.8, 6.5, 3.3 75.2
3.65, ddd, 8.4, 6.6, 3.6 75.1
2.78, dq, 6.9, 6.5
41.6
2.77, apt qn, 7.2
41.6
173.0
108.6
195.7
40.6
87.0
35.1
21.9
11.7
13.3
9.3
172.9
208.2
40.6
87.0
35.1
22.0
11.8
13.2
9.4
2.49, dq, 12.3, 7.0
3.80, dd, 12.3, 3.0
1.74, m
2.49, dq, 12.3, 6.6
3.77, dd, 12.3, 3.3
1.73, m
1.57 and 1.25, m
0.94, t, 7.2
1.50, m
0.98, t, 7.5
1.22, d, 6.9
1.74, s
1.20, d, 7.2
1.73, s
1.08, d, 6.9
1.05, d, 6.9
10.7
16.2
1.08, d, 6.6
1.03, d, 6.6
10.6
16.1
a Chemical shifts and coupling constants as reported in ref 9 (360 MHz).
b NMR spectrometer (600 MHz, CDCl3). Assignments assisted by 1H-13C
HMBC, 1H-13C HMQC, and 1H-1H COSY. c Chemical shifts in ppm
referenced to CHCl3 at 7.26 ppm and to CDCl3 at 77.0 ppm.
the natural product. Because no optical rotation was reported
for the natural product, we were unable to assign the absolute
configuration of the natural product.
1006, 834, 739, 711, 687; [R]20 +7.1 (c 1.1, CHCl3).
D
Conclusions
(4S,5S,6S)-5-tert-Butyldimethylsilyloxy-4,6-dimethyloctan-3-
one (20). To a solution of benzoate 25 (0.82 g, 2.03 mmol) in THF
(24.5 mL) and methanol (12.7 mL) at 0 °C was added (via a
cannula) a solution of samarium diiodide (3-4 eqiv) in THF (0.1
M) until TLC analysis indicated reaction completion. The reac-
tion was quenched by the addition of K2CO3 (sat. aq, 120 mL),
and the product was extracted with Et2O (3 × 150 mL). The
combined extracts were washed with brine (100 mL), dried
(MgSO4), and concentrated in vacuo. The product was purified by
In summary, a highly convergent synthesis of putative
isomeric structures 1-8 for the natural product maurenone has
been achieved by the reaction of ketones 20 and 21 with
aldehydes 16-19. This synthesis used lactate derived ketones
(R)-14 and (S)-14 and (R)-15 and (S)-15 to generate four of the
five required stereocenters in the final products. Comparison
of the H and 13C NMR data reported for the natural product
1
column chromatography (40% CH2Cl2/mixed hexanes, Rf
)
with those for the isomers enabled the assignment of the
0.58), yielding 0.54 g (93%) of 20 as a clear, colorless oil. 1H NMR
(300 MHz, CDCl3) δ 3.83 (1H, dd, J ) 7.8, 2.7 Hz, CH(OTES)),
2.78 (1H, apt qn, J ) 7.2 Hz, C(dO)CH(CH3)), 2.48 (2H, dq, J )
18.3, 7.2 Hz, CH3CH2C(dO)), 1.53-1.41 (1H, m, CH(OTES)-
CH(CH3)), 1.22-1.03 (2H, m, CH(CH3)CH2CH3), 1.00 (3H, t, J
) 7.2 Hz, CH3CH2C(dO)), 0.94 (3H, d, J ) 7.2 Hz, C(dO)CH-
(CH3)), 0.91 (9H, t, J ) 8.1 Hz, Si(CH2CH3)3), 0.90-0.85 (6H, m,
CH(CH3)CH2CH3, CH(CH3)CH2CH3), 0.54 (6H, q, J ) 8.1 Hz,
Si(CH2CH3)3); 13C NMR (75.5 MHz, CDCl3) δ 214.5, 78.7, 49.6,
structure of the natural product as isomer 3.
Experimental Section
(2R,4S,5S,6S)-2-Benzoyloxy-5-hydroxy-4,6-dimethyloctan-3-
one (24). To a solution of dicyclohexylboron chloride (1.58 mL,
7.28 mmol) in Et2O (19.5 mL) at -78 °C was added dimethyl-
ethylamine (0.95 mL, 8.73 mmol) dropwise, followed by ketone
R-15 (1.0 g, 4.85 mmol) in Et2O (19.5 mL). The resulting milky
white solution was slowly warmed to 0 °C and stirred for 2 h before
cooling to -78 °C and adding aldehyde 23 (0.63 g, 7.28 mmol)
dropwise. The solution was stirred for an additional 2 h at -78 °C
before being placed in the freezer overnight. After this time, the
solution was placed in a 0 °C bath and stirred for 30 min. The
reaction was quenched by the addition of methanol (20 mL), pH 7
phosphate buffer (20 mL), and H2O2 (30%, 20 mL) at 0 °C. The
solution was warmed to room temperature and stirred for 2.5 h
before partitioning onto H2O (300 mL) and extracting with
CH2Cl2 (3 × 200 mL). The combined extracts were dried (MgSO4)
and concentrated in vacuo. The product was purified by column
chromatography (100% CH2Cl2, Rf ) 0.26) to yield 1.17 g (83%,
90% ds) of 24 as a white crystalline solid (mp 60-63 °C). 1H NMR
(300 MHz, CDCl3) δ 8.10-8.07 (2H, m, ArH), 7.62-7.57 (1H,
38.7, 36.7, 23.7, 15.7, 13.9, 12.3, 7.3, 6.9, 5.2; IR (film, cm-1
)
2962, 2939, 2879, 1721, 1460, 1414, 1378, 1240, 1133, 1115, 1090,
1058, 1008, 975, 835, 738; [R]20 +33.3 (c 1.1, CHCl3); HRMS
D
(ESI) found 287.2401, C16H34O2SiH+ requires 287.2401; LREIMS
257 (81%), 229 (14%), 201 (10%), 171 (65%), 143 (12%), 115
(14%), 103 (18%), 84 (43%), 75 (31%), 57 (100%), 51 (19%).
(2R,4S,5R)-2-Benzyloxy-5-hydroxy-4-methylheptan-3-one (31).
To a solution of dicyclohexylboron chloride (1.24 mL, 5.72 mmol)
in Et2O (12 mL) at -78 °C was added triethylamine (0.95 mL, 6.8
mmol) dropwise, followed by ketone (R)-14 (0.73 g, 3.79 mmol)
in Et2O (12 mmol). The resulting milky white solution was stirred
at -78 °C for 2 h before the dropwise addition of propanal (22)
(1.1 mL, 15.2 mmol). The solution was stirred for another 2 h at
-78 °C before being placed in the freezer overnight. After this
J. Org. Chem, Vol. 71, No. 1, 2006 121

Crossman and Perkins
time, the solution was placed in a 0 °C bath and stirred for 30 min.
The reaction was quenched by the addition of methanol (12 mL),
pH 7 phosphate buffer (12 mL), and H2O2 (30%, 12 mL)) at 0 °C.
The solution was warmed to room temperature and stirred for 1 h
before extracting the product with CH2Cl2 (3 × 100 mL). The
combined extracts were dried (MgSO4) and concentrated in vacuo.
The product was purified by column chromatography (50% Et2O/
CH2Cl2, Rf ) 0.34), yielding 0.69 g (73%, 95% ds) of adduct 31 as
(3H, s, Si(CH3)A(CH3)B), 0.08 (3H, s, Si(CH3)A(CH3)B); 13C
NMR (75.5 MHz, CDCl3) δ 138.6, 128.3, 127.6, 127.5, 75.8, 74.9,
73.6, 70.2, 37.8, 26.6, 25.9, 18.1, 12.8, 10.6, 9.8, -4.1, -4.6; IR
(film, cm-1) 3569, 3486, 2959, 2932, 2885, 2858, 1472, 1463, 1456,
1383, 1253, 1073, 1046, 1028, 1005, 983, 834, 775, 734, 697, 667;
[R]20 +1.99 (c 1.5, CHCl3); HRMS (ESI) found 267.2664,
D
C21H38O3SiNa+ requires 267.2663; LREIMS 231 (7%), 201
(15%), 191 (19%), 181 (23%), 173 (46%), 159 (8%), 143 (7%),
133 (12%), 115 (14%), 91 (100%), 84 (26%), 75 (27%), 57 (20%),
55 (12%). Minor isomer (2R,3R,4S,5R) (33b): 1H NMR (300 MHz,
CDCl3) δ 7.36-7.27 (5H, m, ArH), 4.67 (1H, d, J ) 11.4 Hz,
OCHAHBPh), 4.45 (1H, d, J ) 11.4 Hz, OCHAHBPh), 3.64 (1H,
apt q, J ) 5.4 Hz, CH(OTBS)), 3.57-3.53 (2H, m, CH(OH),
CH(CH3)OBn), 1.74-1.63 (1H, m, CH(OTBS)CH(CH3)), 1.63-
1.50 (2H, m, CH3CH2), 0.90 (3H, d, J ) 8.4 Hz, CH(OTBS)CH-
(CH3)), 0.89 (9H, s, SiC(CH3)3), 0.84 (3H, t, J ) 7.5 Hz, CH3CH2),
0.05 (3H, s, Si(CH3)A(CH3)B), 0.03 (3H, s, Si(CH3)A(CH3)B); 13C
NMR (75.5 MHz, CDCl3) δ 138.4, 128.4, 127.8, 127.7, 77.1, 75.6,
75.2, 71.1, 38.0, 26.4, 25.9, 18.1, 15.5, 9.0, 8.9, -4.1, -4.5; IR
(film, cm-1) 3578, 2960, 2931, 2885, 2858, 1463, 1456, 1255, 1080,
1064, 1027, 1012, 1006, 836, 773, 697, 674, 667; [R]20D -19.8 (c
1.2, CHCl3).
1
a clear, colorless oil. H NMR (300 MHz, CDCl3) δ 7.40-7.29
(5H, m, ArH), 4.57 (1H, d, J ) 11.7 Hz, OCHAHBPh), 4.51 (1H,
d, J ) 11.7 Hz, OCHAHBPh), 4.06 (1H, q, J ) 6.9 Hz, C(dO)-
CH(CH3)O), 3.76 (1H, ddd, J ) 8.1, 5.1, 3.0 Hz, CH3CH2CH(OH)),
3.01 (1H, dq, J ) 7.2, 3.0 Hz, CH(OH)CH(CH3)C(dO)), 2.31 (1H,
s, OH), 1.56-1.28 (2H, m, CH3CH2), 1.38 (3H, d, J ) 6.9 Hz,
C(dO)CH(CH3)O), 1.12 (3H, d, J ) 7.2 Hz, CH(OH)CH(CH3)-
C(dO)), 0.93 (3H, t, J ) 7.5 Hz, CH3CH2CH(OH)); 13C NMR
(75.5 MHz, CDCl3) δ 217.1, 137.5, 128.5, 128.0, 127.8, 79.5, 72.5,
71.7, 44.8, 26.9, 17.3, 10.4, 10.0; IR (film, cm-1) 3467, 2976, 2937,
2880, 1716, 1456, 1373, 1116, 1027, 973, 736, 698; [R]20D +18.1
(c 1.0, CHCl3); HRMS (ESI) found 273.1471, C15H23O3Na+ requires
273.1416; LREIMS 181 (7%), 144 (10%), 135 (11%), 91 (100%),
69 (11%), 65 (12%), 59 (14%), 57.
(2R,3R,4S,5R)-5-tert-Butylsilyloxy-4-methyl-heptan-2,3-diol
(34a). To a solution of benzyl ether 33a (0.58 g, 1.58 mmol) in
ethanol (16 mL), under an atmosphere of nitrogen, was added
palladium on activated carbon (10%, 60 mg). The flask was flushed
with nitrogen followed by hydrogen, and the solution was stirred
under an atmosphere of hydrogen for 2 h or until TLC analysis
indicated that SM was consumed. The reaction mixture was diluted
with ether (60 mL) and filtered through a pad of Celite and
concentrated in vacuo to yield 0.44 g (99%) of 34a as a clear,
(2R,4S,5R)-2-Benzyloxy-5-tertbutyldimethylsilyloxy-4-meth-
ylheptan-3-one (32). To a solution of alcohol 31 (0.69 g, 2.77
mmol) in CH2Cl2 (30 mL) at -78 °C was added 2,6-lutidine (640
µL, 5.48 mmol) dropwise, followed immediately by TBSOTf (0.95
mL, 4.12 mmol). The resulting solution was stirred at -78 °C for
1 h before quenching with NaHCO3 (sat. aq, 70 mL). The product
was extracted with CH2Cl2 (3 × 70 mL), dried (MgSO4), and
concentrated in vacuo. The product was purified by column
chromatography (20% mixed hexanes/CH2Cl2, Rf ) 0.50), yielding
1
1
colorless oil. H NMR (300 MHz, CDCl3) δ 3.77-3.67 (3H, m,
0.89 g (88%) of silyl ether 32 as a clear colorless oil. H NMR
CH(CH3)OH, CH(OH), CH(OTBS)), 1.78-1.68 (1H, m, CH(CH3)),
1.62-1.52 (2H, m, CH(OTBS)CH2), 1.45 (3H, d, J ) 6.3 Hz, CH-
(CH3)OH), 0.94 (3H, t, J ) 7.2 Hz, CH2CH3), 0.91 (9H, s, OSiC-
(CH3)3), 0.77 (3H, d, J ) 7.2 Hz, CH(CH3)), 0.11 (3H, s,
OSi(CH3)A(CH3)B), 0.09 (3H, s, OSi(CH3)A(CH3)B); 13C NMR (75.5
MHz, CDCl3) δ 79.1, 75.9, 68.8, 39.3, 25.8, 24.3, 18.4, 15.5, 12.4,
11.3, -4.5, -4.6; IR (film, cm-1) 3423, 2961, 2934, 2885, 2860,
1473, 1464, 1385, 1255, 1130, 1105, 1069, 1046, 1016, 1003, 987,
(300 MHz, CDCl3) δ 7.37-7.27 (5H, m, ArH), 4.56 (1H, d, J )
11.7 Hz, OCHAHBPh), 4.52 (1H, d, J ) 11.7 Hz, OCHAHBPh),
4.08 (1H, q, J ) 6.6 Hz, C(dO)CH(CH3)OBn), 3.95 (1H, apt q, J
) 5.7 Hz, CH(OTBS)), 3.08 (1H, apt qn, J ) 6.9 Hz, CH(OTBS)-
CH(CH3)), 1.56-1.32 (2H, m, CH3CH2), 1.35 (3H, d, J ) 6.6 Hz,
C(dO)CH(CH3)OBn), 1.06 (3H, d, J ) 6.9 Hz, CH(OTBS)-
CH(CH3)), 0.87 (9H, s, SiC(CH3)3), 0.82 (3H, t, J ) 7.5 Hz,
CH3CH2), 0.03 (3H, s, Si(CH3)A(CH3)B), 0.00 (3H, s, Si(CH3)A-
(CH3)B); 13C NMR (75.5 MHz, CDCl3) δ 213.4, 137.7, 128.5, 127.9
(2), 79.0, 73.4, 71.3, 46.4, 28.1, 25.9, 18.1, 16.4, 12.7, 9.1, -4.1,
-4.5; IR (film, cm-1) 2960, 2933, 2898, 2883, 2858, 1720, 1473,
1465, 1255, 1120, 1105, 1046, 1030, 1006, 991, 835, 775, 736,
870, 836, 776, 675, 667; [R]20 +20.6 (c 1.6, CHCl3).
D
(2R,3S,4S,5R)-5-tert-Butylsilyloxy-4-methyl-heptan-2,3-diol
(34b). Per the procedure for 34a, benzyl ether 33b (0.22 g, 5.88
mmol) was used to yield 0.15 g (91%,) of alcohol 34b as a white
semisolid. 1H NMR (300 MHz, CDCl3) δ 3.81-3.72 (2H, m,
CH(OTBS), CH(CH3)OH), 3.44 (1H, dd, J ) 2.1, 7.2 Hz, CH(OH)),
2.87 (2H, br s, OH, OH), 1.75-1.66 (1H, m, CH(OH)CH(CH3)),
1.60-1.50 (2H, m, CH(OTBS)CH2), 1.14 (3H, d, J ) 6.3 Hz,
CH(CH3)OH), 0.89 (9H, s, OSiC(CH3)3), 0.87 (3H, d, J ) 7.2 Hz,
CH(OH)CH(CH3)), 0.83 (3H, t, J ) 7.5 Hz, CH2CH3), 0.09 (6H,
s, OSi(CH3)2); 13C NMR (75.5 MHz, CDCl3) δ 79.4, 78.9, 68.9,
697, 667; [R]20 +39.0 (c 1.1, CHCl3); HRMS (ESI) found
D
387.2327, C21H36O3SiNa+ requires 387.2326; LREISM 249 (40%),
173 (19%), 157 (23%), 143 (10%), 115 (21%), 91 (100%), 76
(18%), 73 (48%).
2-Benzyloxy-5-tertbutyldimethylsilyloxy-4-methylheptan-3-
ol (33). To a cooled (-78 °C) solution of ketone 32 (0.89 g, 2.44
mmol) in THF (30 mL) was added a solution of LiBH4 (2M in
THF, 7.3 mL, 14.6 mmol) dropwise. The reaction mixture was
placed in an ice bath for 10 min before warming it slowly to room
temperature. After stirring overnight, the solution was cooled to 0
°C before quenching by the addition of H2O (50 mL). The product
was extracted with Et2O (4 × 50 mL). The combined Et2O extracts
were washed with brine (60 mL), dried (MgSO4), and concentrated
in vacuo. The product was purified by column chromatography
(80% CH2Cl2/mixed hexanes, Rf ) 0.42 and 0.36) to yield major
isomer 33a (0.65 g, 65%) and minor isomer 33b (0.24 g, 24%) as
36.4, 27.0, 25.9, 18.8, 18.0, 9.8, 6.5, -3.7, -4.5; IR (film, cm-1
)
3401, 2961, 2932, 2885, 2859, 1473, 1464, 1381, 1362, 1256, 1132,
1103, 1078, 1051, 1014, 1006, 984, 860, 872, 836, 792, 773, 676,
667; [R]20 -11.5 (c 1.5, CHCl3); HRMS (ESI) found 277.2195,
D
C14H22O3SiH+ requires 277.2193; LREIMS 201 (35%), 173 (67%),
143 (17%), 133 (51%), 115 (41%), 75 (100%), 73 (64%), 57 (26%).
(2S,3R)-3-tert-Butyldimethylsilyloxy-2-methylpentanal (18).
To a stirred solution of diols 34a and 34b (0.44 g, 1.58 mmol) in
MeOH (16 mL) and H2O (8 mL) at room temperature was added
NaIO4 (2.06 g, 9.6 mmol), and the resulting suspension was stirred
for 15 min at room temperature. The reaction mixture was diluted
with H2O and extracted with Et2O (3 × 60 mL). The combined
extracts were dried (MgSO4) and concentrated in vacuo. The product
was purified by column chromatography (10% Et2O/mixed hexanes,
Rf ) 0.45) to give 0.35 g (97%) of aldehyde 18 as a clear, color-
1
clear, colorless oils. Major isomer (2R,3S,4S,5R) (33a): H NMR
(300 MHz, CDCl3) δ 7.35-7.25 (5H, m, ArH), 4.60 (1H, d, J )
12.0 Hz, OCHAHBPh), 4.53 (1H, d, J ) 12.0 Hz, OCHAHBPh),
3.92 (1H, dt, J ) 2.1, 7.2 Hz, CH(OTBS)), 3.80 (1H, dd, J ) 3.6,
9.0 Hz, CH(OH)), 3.57 (1H, dq, J ) 3.6, 6.3 Hz, CH(CH3)OBn),
1.68 (1H, dqd, J ) 3.0, 7.2, 10.2 Hz, CH(OTBS)CH(CH3)), 1.52
(2H, m, CH3CH2CH(OTBS)), 1.20 (3H, d, J ) 6.3 Hz, CH(OH)-
CH(CH3)OBn), 0.91 (9H, s, SiC(CH3)3), 0.87 (3H, t, J ) 7.5 Hz,
CH3CH2), 0.76 (3H, d, J ) 7.2 Hz, CH(OTBS)CH(CH3)), 0.10
1
less oil. H NMR (300 MHz, CDCl3) δ 9.76 (1H, d, J ) 0.9 Hz,
CH(dO)), 4.03 (1H, dt, J ) 3.6, 6.6 Hz, CH(OTBS)), 2.46 (1H,
ddq, J ) 0.9, 3.6, 6.9 Hz, CH(dO)CH(CH3)), 1.64-1.45 (2H, m,
122 J. Org. Chem., Vol. 71, No. 1, 2006

Structural Elucidation of (-)-Maurenone
CH(OTBS)CH2), 1.05 (3H, d, J ) 6.9 Hz, CH(dO)CH(CH3)), 0.88
(3H, t, J ) 7.5 Hz, CH2CH3), 0.86 (9H, s, OSiC(CH3)3), 0.06 (3H,
s, OSi(CH3)A(CH3)B), 0.03 (3H, s, OSi(CH3)A(CH3)B); 13C NMR
(75.5 MHz, CDCl3) δ 205.5, 73.4, 50.8, 27.4, 25.7, 18.0, 10.1, 7.6,
-4.2, -4.7; IR (film, cm-1) 2960, 2933, 2884, 2860, 1727, 1473,
NaHSO4 (1 M, 10 mL), H2O (10 mL), NaHCO3 (sat aq., 10 mL),
and brine (10 mL), dried (MgSO4), and concentrated in vacuo.
(Alternatively, the reaction was quenched by the addition of
NH4Cl (sat. aq, 20 mL), and the product was extracted with
CH2Cl2 (3 × 20 mL)). The combined extracts were dried (MgSO4)
and concentrated in vacuo and purified by column chromatog-
raphy to give product 36 (85 mg, 79%). 1H NMR (300 MHz,
CDCl3) (predominantly keto form) δ 4.00 (1H, q, J ) 7.2 Hz,
C(dO)CH(CH3)C(dO)), 3.86 (1H, apt q, J ) 5.7 Hz, CH(OTBS)),
3.75 (1H, dd, J ) 8.4, 2.4 Hz, CH(OTES)), 2.93 (1H, qd, J )
6.9. 6.0 Hz, CH(OTBS)CH(CH3)), 2.83 (1H, dq, J ) 8.7, 6.9 Hz,
C(dO)CH(CH3)CH(OTES)), 1.67-1.12 (5H, m, CH3CH2, CH(CH3)-
CH2CH3, CH(CH3)CH2CH3), 1.26 (3H, d, J ) 7.2 Hz, C(dO)CH-
(CH3)C(dO)), 1.08 (3H, d, J ) 6.9 Hz, CH(OTBS)CH(CH3)-
C(dO)), 1.01 (3H, d, J ) 6.9 Hz, C(dO)CH(CH3)CH(OTES)),
0.95-0.86 (18H, m, Si(CH2CH3)3), CH3CH2, CH2CH3, CH(OTES)-
CH(CH3)CH2), 0.91 (9H, s, SiC(CH3)3), 0.53 (6H, q, J ) 8.1
Hz, Si(CH2CH3)3), 0.083 (3H, s, Si(CH3)A(CH3)B), 0.075 (3H, s,
Si(CH3)A(CH3)B); 13C NMR (75.5 MHz, CDCl3) δ 212.2, 210.2,
80.0, 74.5, 61.8, 49.7, 49.4, 40.1, 27.6, 25.9, 24.6, 18.2, 15.2, 14.2,
13.8, 12.6, 12.2, 9.4, 6.9, 5.2, -4.3, -4.4; IR (film, cm-1) 2960,
2937, 2879, 2860, 1727, 1701, 1462, 1379, 1362, 1254, 1130, 1115,
1054, 1005, 873, 836, 793, 776, 738, 725, 673.
1464, 1254, 1141, 1103, 1048, 1030, 1006, 837, 775, 667; [R]20
D
+53.7 (c 0.7, CHCl3).
(3S,4S,5S,7R/S,9R/S,9S,10R)-10-tert-Butyldimethylsilyloxy-4-
triethylsilyloxy-8-hydroxy-3,5,7,9-tetramethyldodeca-6-one (35).
To a solution of ketone 20 (105 mg, 0.368 mmol) in THF (0.74
mL) at -78 °C was added a solution of lithium bis(trimethylsilyl)-
amide (1 M in THF, 552 µL, 0.552 mmol) dropwise. The resulting
yellow solution was stirred at -78 °C for 30 min and then warmed
to -50 °C for 30 min. The solution was then cooled to -78 °C,
and aldehyde 18 (127 mg, 0.552 mmol) was added. The resulting
solution was stirred at -78 °C for 2 h. The reaction was quenched
by the addition of pH 7 phosphate buffer solution (2 mL), and the
organics were extracted with Et2O (5 × 5 mL). The combined
extracts were washed with brine (5 mL), dried (MgSO4), and
concentrated in vacuo. The product was purified by column
chromatography (5% Et2O/hexanes, Rf ) 0.21, 0.13 and 0.05) to
yield 108 mg (57%) of aldol adduct 35 as a mixture of diastereomers
(0.74:0.08:0.18) and clear, colorless oils. 35a: 1H NMR (600 MHz,
CDCl3) δ 4.04-3.98 (2H, m, CH(OH), CH(OTBS)), 3.87 (1H, dd,
J ) 8.1, 3.0 Hz, CH(OTES)), 3.32 (1H, br s, OH), 3.06 (1H, dq,
J ) 7.8, 6.9 Hz, C(dO)CH(CH3)CH(OTES)), 2.63 (1H, qd, J )
7.2, 1.8 Hz, CH(OH)CH(CH3)C(dO)), 1.63-1.43 (6H, m, CH3CH2,
CH(OTBS)CH(CH3), CH(OTES)CH(CH3), CH2CH3), 1.15 (3H,
d, J ) 7.5 Hz, CH(OH)CH(CH3)C(dO)), 0.98-0.83 (12H, m,
CH3CH2, CH2CH3, C(dO)CH(CH3)CH(OTES), CH(OTES)CH-
(CH3)CH2), 0.93 (9H, t, J ) 7.5 Hz, Si(CH2CH3)3), 0.88 (9H, s,
SiC(CH3)3), 0.72 (3H, d, J ) 6.6 Hz, CH(OTBS)CH(CH3)CH(OH)),
0.55 (6H, q, J ) 7.5 Hz, Si(CH2CH3)3), 0.09 (3H, s, Si(CH3)A-
(CH3)B), 0.07 (3H, s, Si(CH3)A(CH3)B); 13C NMR (75.5 MHz,
CDCl3) δ 219.1, 79.1, 73.0, 70.6, 48.6, 47.3, 39.3, 38.0, 27.4, 25.9,
24.4, 18.1, 15.4, 14.0, 12.5, 10.6, 9.0, 8.0, 7.0, 5.3, -4.4, -4.5; IR
(film, cm-1) 3533, 2961, 2938, 2880, 2859, 1699, 1463, 1381, 1251,
1150, 1130, 1107, 1059, 1006, 973, 871, 835, 775, 739, 729, 666;
(2S,3S)-2,3-Dihydro-6-[1S,2R]-(2-tertbutyldimethylsilyloxy-1-
methylbutyl)-2-[1S]-(1-methylpropyl)-3,5-dimethyl-pyran-4-
one (37). To a solution of dione 36 (88.6 mg, 0.172 mmol) in CDCl3
(3 mL) was added trifluoroacetic acid (5 drops) at room temperature
with stirring. The solution was stirred for approximately 1 h or
until TLC analysis showed the consumption of starting ma-
terial. The solution was diluted with Et2O (50 mL), washed with
NaHCO3 (sat. aq, 30 mL) and brine (30 mL), dried (MgSO4), and
concentrated in vacuo. The product was purified by column
chromatography (100% CH2Cl2, Rf ) 0.31), yielding 41.7 mg (63%)
1
of compound 37 as a clear, colorless oil. H NMR (300 MHz,
CDCl3) δ 3.81 (1H, dt, J ) 9.0, 4.2 Hz, CH(OTBS)), 3.71 (1H,
dd, J ) 12.3, 3.3 Hz, CH(CH3)CH(O)CH(CH3)), 2.81 (1H, dq, J
) 9.0, 7.2 Hz, CH(OTBS)CH(CH3)), 2.46 (1H, dq J ) 12.3, 6.9
Hz, C(dO)CH(CH3)CH(O)), 1.74 (3H, s, C(O)dC(CH3)C(dO)),
1.80-1.66 (1H, m, CH(O)CH(CH3)CH2), 1.62-1.44 (2H, m,
CH3CHAHBCH(OTBS), CH(CH3)CHAHBCH3), 1.41-1.19 (2H, m,
CH3CHAHBCH(OTBS), CH(CH3)CHAHBCH3), 1.14 (3H, d, J )
7.2 Hz, CH(OTBS)CH(CH3)), 1.06 (3H, d, J ) 6.9 Hz, C(dO)-
CH(CH3)CH(O)), 1.02 (3H, d, J ) 6.9 Hz, CH(O)CH(CH3)CH2),
0.94 (3H, t, J ) 7.5 Hz, CH(CH3)CH2CH3), 0.90 (9H, s, SiC(CH3)3),
0.84 (3H, t, J ) 7.2 Hz, CH3CH2), 0.07 (3H, s, Si(CH3)A(CH3)B),
0.06 (3H, s, Si(CH3)A(CH3)B); 13C NMR (75.5 MHz, CDCl3) δ
195.9, 173.4, 108.6, 86.6, 74.5, 41.2, 40.5, 35.2, 27.8, 25.9, 22.0,
[R]20 +52.1 (c 0.9, CHCl3). 35b: Not characterized because a
D
small amount was isolated. 35c: 1H NMR (600 MHz, CDCl3) δ
3.95 (1H, apt t, J ) 5.4 Hz, CH(OH)), 3.93 (1H, dd, J ) 6.0, 2.7
Hz, CH(OTES)), 3.71 (1H, ddd, J ) 8.4, 6.0, 2.4 Hz, CH(OTBS)),
2.96 (1H, dq, J ) 8.4, 7.5 Hz, C(dO)CH(CH3)CH(OTES)),
2.86 (1H, qd, J ) 7.2, 6.0 Hz, CH(OH)CH(CH3)C(dO)), 1.65-
1.46 (5H, m, CH3CHAHB or CHAHBCH3, CH3CH2 or CH2CH3,
CH(OTBS)CH(CH3), CH(OTES)CH(CH3)), 1.22-1.12 (1H, m,
CH3CHAHB or CHAHBCH3), 1.16 (3H, d, J ) 7.2 Hz, CH(OH)-
CH(CH3)C(dO)), 0.97-0.78 (15H, m, CH(OTBS)CH(CH3),
C(dO)CH(CH3), CH(OTES)CH(CH3), CH3CH2, CH2CH3), 0.94
(9H, t, J ) 8.1 Hz, Si(CH2CH3)3), 0.90 (9H, s, SiC(CH3)3), 0.59
(6H, q, J ) 8.1 Hz, Si(CH2CH3)3), 0.11 (3H, s, Si(CH3)A(CH3)B),
0.09 (3H, s, Si(CH3)A(CH3)B); 13C NMR (75.5 MHz, CDCl3) δ
216.6, 77.54, 77.51, 74.1, 49.2, 48.9, 39.1, 37.5, 27.4, 25.9, 24.3,
18.0, 15.7, 13.7, 12.6, 11.0, 10.2, 7.4, 7.0, 5.3, -3.7, -4.4; IR (film,
cm-1) 3524, 2961, 2938, 2879, 2861, 1712, 1463, 1415, 1380, 1361,
1255, 1132, 1113, 1056, 1006, 977, 872, 835, 814, 774, 738, 667;
18.2, 16.1 (2), 11.8, 10.6, 9.4, 8.0, -4.2, -4.5; IR (film, cm-1
)
2962, 2933, 2881, 2859, 1668, 1618, 1472, 1462, 1376, 1359, 1354,
1254, 1191, 1157, 1144, 1106, 1073, 1054, 1035, 1005, 879, 856,
836, 794, 775, 675; [R]20 -99.8 (c 0.4, CHCl3).
D
(2S,3S)-2,3-Dihydro-6-[(1′S,2′R)-2-hydroxy-1-methylbutyl]-
3,5-dimethyl-2-[(1′′S)-1-methylpropyl]-4H-pyran-4-one (3). A
solution of silyl ether 36 (41.7 mg, 0.109 mmol) in HF/pyr/pyr
(750 µL; from a stock solution containing dry THF (10 mL),
pyridine (5 mL), and pyridinium hydrofluoride (2.1 g)) and H2O
(80 µL) was stirred at room temperature in a Teflon-screw-cap jar
for 12 days or until TLC indicated the consumption of starting
material. The solution was diluted with Et2O (30 mL), washed with
CuSO4 (sat. aq, 15 mL), NaHCO3 (sat. aq, 15 mL), and brine (15
mL), dried (MgSO4), and concentrated in vacuo. The product was
purified by column chromatography (10% Et2O/CH2Cl2, Rf ) 0.33),
[R]20 -2.47 (c 2.0, CHCl3).
D
(3R,4S,8S,9S,10S)-3-tert-Butyldimethylsilyloxy-4,6,8,10-tet-
ramethyl-9-triethylsilyloxydodecane-5,7-dione (36). Oxalyl chlo-
ride (152 µL, 0.305 mmol) was added dropwise to a solution of
DMSO (43 µL, 0.609 mmol) in CH2Cl2 (870 µL) at -78 °C, and
the solution was stirred for 30 min. Alcohol 35 (108 mgs, 0.209
mmol) was added via a cannula, and the resulting solution was
stirred for 45 min at -78 °C. Et3N (170 µL, 0.122 mmol) was
then added dropwise over several minutes and stirred at -78 °C
for 30 min before warming to 0 °C and stirring for 1 h. The reaction
was quenched by pouring onto NaHSO4 (1 M, 10 mL). The aqueous
layer was extracted with Et2O (3 × 20 mL). The combined organics
were concentrated in vacuo, taken up in Et2O (50 mL), washed in
1
yielding 26.4 mg (90%) of product 3 as a clear, colorless oil. H
NMR (300 MHz, CDCl3) δ 3.77 (1H, dd, J ) 12.3, 3.3 Hz, CH(O)-
CH(CH3)CH2CH3), 3.65 (1H, ddd, J ) 8.4, 6.6, 3.9 Hz, CH(OH)),
2.77 (1H, apt qn, J ) 7.2 Hz, CH(OH)CH(CH3)), 2.49 (1H, dq, J
) 12.3, 6.6 Hz, C(dO)CH(CH3)), 1.88 (1H, br s, OH), 1.73 (3H,
s, C(O)dC(CH3)C(dO)), 1.76-1.70 (1H, m, CH(O)CH(CH3)-
CH2CH3), 1.60-1.53 (1H, m, CH(CH3)CHAHBCH3), 1.52-1.45
J. Org. Chem, Vol. 71, No. 1, 2006 123

Crossman and Perkins
(1H, m, CH3CHAHBCH(OH)), 1.43-1.35 (1H, m, CH3HAHBCH-
(OH)), 1.28-1.22 (1H, m, CH(CH3)CHAHBCH3)), 1.20 (3H, d, J
) 7.2 Hz, CH(OH)CH(CH3)), 1.08 (3H, d, J ) 6.6 Hz, C(dO)-
CH(CH3)), 1.03 (3H, d, J ) 6.6 Hz, CH(CH3)CH2CH3), 0.96
(3H, t, J ) 7.2 Hz, CH3CH2CH(OH), 0.94 (3H, d, J ) 7.2 Hz,
CH(CH3)CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 195.7, 173.0,
108.6, 87.0, 75.1, 41.6, 40.6, 35.1, 28.0, 22.0, 16.2, 13.2, 11.7, 10.6,
Sincich, Center for Marine Biotechnology and Biomedicine,
Scripps Institution of Oceanography and Dr. Denise Manker
for correspondence regarding copies of the original H NMR
spectra of maurenone from the original isolation. J.S.C. ac-
knowledges the receipt of an Australian Post Graduate Award.
1
Supporting Information Available: General experimental
details, detailed experimental procedures, spectroscopic data for
compounds 1, 2, 4-8, 16, 17, 19, 21, and 26-30, and copies of
1H and 13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
10.2, 9.3. H and 13C NMR (600 MHz, CDCl3) reported in Table
1. IR (film, cm-1) 3435, 2967, 2935, 2878, 1664, 1650, 1609, 1459,
1378, 1357, 1196, 1144, 1070, 1029, 977; [R]20 -137.5 (c 0.9,
D
CHCl3), UV (CHCl3) 275 nm (ꢀ 20 100).
Acknowledgment. We thank Flinders University for finan-
cial support and facilities. We also thank Ms. Catherine M.
JO051753C
124 J. Org. Chem., Vol. 71, No. 1, 2006