Synthetic efforts toward the spiroketal core of spirangien a

Article abstract of DOI:10.1021/jo100871m

(Figure presented) Synthetic studies toward the spiroketal core of spirangien A are described. Two synthetic approaches were developed. Both of them use a diastereoselective aldol addition of a lithium enolate derived from a methyl ketone on an aldehyde. In the first approach, the introduction of the (E)-trisubstituted terminal olefin was achieved by using an iron-catalyzed cross-coupling between an alkyl iodide and a vinyl Grignard reagent and a randomly protected spiroketal was obtained. In the second approach, a highly functionalized spiroketal carbamate, which includes 13 stereogenic centers, was successfully isolated.

Full text of DOI:10.1021/jo100871m

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Synthetic Efforts toward the Spiroketal Core of Spirangien A
†
Amandine Guerinot, Guillaume Lepesqueux, Serge Sable,
†
ꢀ
Sebastien Reymond,* and Janine Cossy*
ꢀ ‡
,†
,†
ꢀ
†Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10 rue Vauquelin,
75231 Paris Cedex 05, France, and ‡Sanofi-Aventis, Centre de recherche de Vitry-Alfortville,
9 Quai Jules Guesde, 94400 Vitry sur Seine, France
janine.cossy@espci.fr; sebastien.reymond@espci.fr
Received May 5, 2010
Synthetic studies toward the spiroketal core of spirangien A are described. Two synthetic approaches
were developed. Both of them use a diastereoselective aldol addition of a lithium enolate derived from a
methyl ketone on an aldehyde. In the first approach, the introduction of the (E)-trisubstituted terminal
olefin was achieved by using an iron-catalyzed cross-coupling between an alkyl iodide and a vinyl
Grignard reagent and a randomly protected spiroketal was obtained. In the second approach, a highly
functionalized spiroketal carbamate, which includes 13 stereogenic centers, was successfully isolated.
Introduction
the gene cluster2 and finally confirmed by Paterson et al. by
total synthesis.3 Compared to spirangien A, the cytotoxicity
of this simplified and more stable spiroketal 1 remains high
(IC50 =13 pM). Thus, the biological activity of the latter as
well as the synthetic challenge related to its original structure
has solicited interest among organic chemists, and in 2008,
the first total synthesis of spirangien A was published by
Paterson et al.3,4 On the basis of its unique architectural fea-
tures, we embarked on the elaboration of spiroketal 1, and
herein we would like to report a full account of our synthetic
efforts.
Spirangiens A and B are polyketide metabolites isolated
from the epothilone-producing myxobacterium Sorangium
cellulosum (strain So ce90) (Scheme 1). These unique natural
products display a significant in vitro cytotoxicity (IC50=1 pM
against L929 mouse fibroblast cell line), as well as potent anti-
biotic and antifungal activities.1 Spirangiens A and B possess
14 stereogenic centers and include a highly functionalized
spiroketal core bearing two lateral side chains. One of them is
constituted by a conjugated pentaenic moiety and a terminal
carboxylic acid. The second one is ended by a trisubstituted
double bond. Spirangiens A and B only differ by the substi-
tuent of the double bond at C31 (methyl or ethyl group). The
structure of these natural products was determined by NMR
studies and mass spectrometry. In order to establish the rela-
tive configuration of the 14 stereocenters, spirangien A was
treated with ethylene in the presence of the second-generation
Grubbs catalyst affording spiroketal 1 as the major product,
and an X-ray crystal structure analysis of the latter furnished
a secure determination of the relative stereochemistry (Scheme 1).
The absolute configuration was hypothesized by analysis of
Results and Discussion
First Strategy. In our retrosynthetic study of spiroketal 1,
the introduction of the (Z)-diene unit was planned to be per-
formed at a late stage (Scheme 2). In order to form the spiroketal
moiety, a one-pot deprotection/spiroketalization sequence
applied to the linear precursor A was envisioned, and the C21
€
(2) Frank, B.; Knauber, J.; Steinmetz, H.; Scharfe, M.; Blocker, H.;
€
Beyer, S.; Muller, R. Chem. Biol. 2007, 14, 221.
(3) Paterson, I.; Findlay, A. D.; Anderson, E. A. Angew. Chem., Int. Ed.
2007, 46, 6699.
€
(1) (a) Niggeman, J. N.; Bedorf, N.; Florke, U.; Steinmetz, H.; Gerth, K.;
(4) (a) Lorenz, M.; Kalesse, M. Tetrahedron Lett. 2007, 48, 2905. (b) Lorenz,
M.; Kalesse, M. Org. Lett. 2008, 10, 4371. (c) Paterson, I.; Findlay, A.; Noti, C.
Chem. Commun. 2008, 6408. (d)Paterson, I.;Findlay, A.;Noti, C.Chem.-Asian J.
2009, 4, 594.
€
€
Reichenbach, H.; Hofle, G. Eur. J. Org. Chem. 2005, 5013. (b) Hofle, G.;
Bedorf, N.; Gerth, K.; Reichenbach, H. DE-4211056, 1993; Chem. Abstr. 1993,
119, 180598.
DOI: 10.1021/jo100871m
r
Published on Web 07/08/2010
J. Org. Chem. 2010, 75, 5151–5163 5151
2010 American Chemical Society

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SCHEME 1
SCHEME 2
stereocenter would be controlled by taking advantage of a
double anomeric effect. Fragment A would be assembled by
an aldolisation between aldehyde B and methyl ketone C.
The terminal trisubstituted double bond in aldehyde B could
be introduced according to our recently reported iron-catalyzed
cross-coupling between alkyl halides and alkenyl Grignard
reagents that would be applied to alkyl iodide D.5 The C24-
C28 stereopentad would be built by using two consecutive
stereoselective crotyltitanations applied to aldehyde E, which
would be easily prepared from the (R)-Roche ester. The C20
stereogenic center in ketone C would be controlled by a
stereoselective reduction of propargylic ketone F, which would
be prepared from diol G synthesized according to reported
procedures.6,7
As depicted in Scheme 3, the synthesis of the C13-C22
fragment of spiroketal 1 started with the tert-butyldimethyl-
silyl (TBS) protection of diol 28 to yield olefin 3 (TBSOTf,
2,6-lutidine, -78 °C, CH2Cl2, 89%). A regioselective hydro-
boration of the C19-C20 double bond was applied to 3, and
alcohol 4 was produced (BH3 THF, rt, THF then H2O2,
3
NaOH, 62%). This latter was oxidized to an aldehyde (Dess-
Martin periodinane, rt, CH2Cl2) and after addition of ethynyl-
magnesium bromide, the resulting secondary alcohol was oxi-
dized to the corresponding propargylic ketone 5 (3 steps, 61%
yield). In order to control the C20 stereocenter, a diastereo-
selective reduction of propargylic ketone 5 was achieved with
ꢀ
(5) (a) Guerinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2007,
ꢀ
ꢀ
46, 6521. (b) Reymond, S.; Ferrie, L.; Guerinot, A.; Capdevielle, P.; Cossy, J.
Pure Appl. Chem. 2008, 80, 1665. (c) See also: Cahiez, G.; Duplais, C.;
Moyeux, A. Org. Lett. 2007, 9, 3253.
(6) (a) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321. (b) BouzBouz, S.;
Cossy, J. Org. Lett. 2001, 3, 3995.
(7) (a) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105, 2487.
(b) Harada, T.; Matsuda, Y.; Wada, I.; Uchimura, J.; Oku, A. J. Chem. Soc.,
Chem. Commun. 1990, 21.
(8) Obtained from meso-diol (2R*,3S*,4S*)-3-(tert-butyldimethylsilyl-
oxy)-2,4-dimethyl-1,5-pentanediol 32 according to reported procedures;
see refs 6 and 7.
(S)-Me-CBS oxazaborolidine in the presence of BH3 Me2S
3
complex to afford the desired alcohol as a mixture of two diastereo-
mers (dr = 97/3).9,10 After separation by flash chromatography
(9) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925. (c) Corey, E. J.; Shibata, S.; Bakshi,
R. K. J. Org. Chem. 1988, 53, 2861. (d) For a review, see: Corey, E. J.; Helal,
C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (e) For application to propargylic
ketones, see: Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
(10) The diastereomeric ratio was determined by 1H NMR analysis and/
or GC/MS analysis of the crude reaction mixture.
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SCHEME 3
SCHEME 4
on silica gel, alcohol 6 was isolated (dr >98/2, 86% yield) and
subsequently protected, giving rise to 7 (TBSOTf, 2,6-lutidine,
-78 °C, CH2Cl2, 97%). In order to complete the synthesis of
methyl ketone 8, an hydration of the triple bond has to be
performed. At this stage, difficulties were encountered due to
the required acidic conditions for the hydration of the triple
bond and the lability of the silyl ethers. Several set of conditions
were evaluated, and the best results were obtained with
Hg(OAc)2 (0.3 equiv) in the presence of PPTS (0.5 equiv)
in a THF/H2O mixture (41%).11,12
Our efforts were then directed to the preparation of the
second aldol coupling partner B which started with the trans-
formation of the (R)-Roche ester to aldehyde 913 (TBDPSCl,
imidazole then DIBAL-H, -78 °C, hexanes, 84% for the 2 steps)
(Scheme 4). In order to control the C25 and C26 stereogenic
centers, a first stereoselective crotyltitanation using (S,S)-Ti-I
was performed (-78 °C, Et2O), and the corresponding homo-
allylic alcohol 10 was obtained in 71% yield with a good
€
(11) For recent examples in synthesis, see: (a) Witulski, B.; Bergstraber,
U.; Gossmann, M. Tetrahedron 2000, 56, 4747. (b) Paterson, I.; Tudge, M.
€
€
Tetrahedron 2003, 59, 6833. (c) Paterson, I.; Muhltau, F. A.; Cordier, C. J.;
Housden, M. P.; Burton, P. M.; Loiseleur, O. Org. Lett. 2009, 11 (2), 353.
(12) Other conditions did not give any satisfactory results; when the
reaction was performed with Hg(SO4)2/AcOH at rt, the cleavage of silyl
ethers was observed. When Hg(SO4)2 was used without any acid at 40 °C, no
conversion of the alkyne was noticed, whereas at 70 °C, the silyl ethers were
cleaved.
(13) Prepared according to a reported procedure by Johns, B. A.; Grant,
C. M.; Marshall, J. M. Organic Synthesis; Wiley: New York, 2004; Collect.
Vol. X, p 170.
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SCHEME 5
SCHEME 6
diastereomeric ratio (dr >95/5).10 After protection of alcohol
10 as a TBS ether, the double bond was oxidatively cleaved
(OsO4, NMO then NaIO4), and the resulting aldehyde was
treated with the crotyltitanium reagent (R,R)-Ti-II to afford
alcohol 12 (72% for the four steps, dr >95/5).10 After TBS
protection (TBSOTf, 2,6-lutidine, -78 °C, CH2Cl2, 90%)
and oxidative cleavage of the double bond (OsO4, NMO then
NaIO4) followed by a sodium borohydride reduction of the
obtained aldehyde, primary alcohol 14 was isolated in 79%
yield (3 steps). This alcohol was subsequently transformed to
the corresponding alkyl iodide 15 under standard conditions
(PPh3, I2, imidazole, rt, CH2Cl2, 97%). At this point, the com-
pletion of the synthesis of aldehyde 18 required only the
introduction of the trisubstituted C30-C31 double bond.
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SCHEME 7
leading to alkene 16 in a good yield of 76%.5 The primary
TBDPS ether was then selectively cleaved (TBAF/AcOH, rt,
THF, 73%),15,16 and the corresponding primary alcohol was
oxidized to give the required aldehyde 18.
With ketone 8 and aldehyde 18 in hand, the challenging
aldol coupling was then examined. In order to favor the anti
Felkin-Anh adduct, the use of a chiral boron enolate was
first evaluated.17 Unfortunately, treatment of ketone 8 with
(-)-Ipc2BCl/Et3N followed by addition of aldehyde 18 did
not afford the aldol product as no conversion of the starting
materials was observed. Gratifyingly, the addition of the lithium
enolate derived from 8 (LDA, -78 °C, THF) on aldehyde 18
provided the aldol adducts with a diastereomeric ratio of 3/1
in favor of the desired diastereomer 19.18 This diastereomeric
ratio is similar to the one obtained by Paterson et al. (using a
chiral boron enolate, dr=2.5/1)3 or Kalesse et al. (using LiHMDS
to generate the methylketone lithium enolate, dr = 3/1).4b How-
ever, in our case, we were able to separate the two isomers by
flash chromatography. In Paterson et al. synthesis, when
LDA was used to generate a methylketone lithium enolate,
the undesired Felkin adduct was obtained in a 3.5/1 ratio, thus
underlining the high substrate dependence on the diastereos-
electivity of this aldol condensation.19 Alcohol 19 was iso-
lated in 45% yield and then transformed to its corresponding
methyl ether 20 (MeOTf, 2,6-di-tert-butylpyridine, 50 °C,
CH2Cl2) with a yield of 50% (Scheme 5).20,21
At this point, the one-pot deprotection/spiroketalization
sequence was investigated. Unfortunately, treatment of the
linear compound 20 with CSA in a CH2Cl2/MeOH mixture
led to the formation of a side product that did not possess
any double bond. Under acidic conditions, the electron-rich
double bond could be activated, and then an intramolecular
nucleophilic attack of the C27 hydroxyl group could proceed
to form a furan ring.22 In order to prevent this side reaction,
(15) (a) Zhu, B.; Panek, J. S. Eur. J. Org. Chem. 2001, 1701. (b) Zhu, B.;
Panek, J. S. Org. Lett. 2000, 2, 2575. (c) Mitchell, I. S.; Pattenden, G.;
Stonehouse, J. P. Tetrahedron Lett. 2002, 43, 493.
(16) No reaction occurred under other conditions such as NH4F in
MeOH.
(17) This method was successfully used by Paterson et al. in their synthesis
of spirangien A. See ref 3 and (a) Paterson, I.; Florence, G. J.; Gerlach, K.;
Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (b) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int. Ed. 2000, 39, 377.
(c) Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron Lett. 1990, 46, 4663.
(18) The diastereomeric ratio was determined by analysis of the 1H NMR
spectrum of the crude product. Assignment of each diastereomer was
hypothesized by analysis of the ABX pattern of the C22 methylene unit;
see: Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwenhze, M. S.;
Gustin, D. J.; Dilley, G. J.; Lane, G. C.; Scheidt, K. A.; Smith, W. J. J. Org.
Chem. 2002, 67, 4284. See Supporting Information for details. The stereo-
chemistry was also confirmed by NOESY studies on spiroketal 22, see
Supporting Information for details.
However, the addition of (E)-1-methyl-1-propenyllithium to
iodide 15 led to the migration of the TBS group from the C27
hydroxyl group to C29, and a mixture of products was
obtained. A Pd-catalyzed Negishi cross-coupling14 was app-
lied to alkyl iodide 15, but unfortunately, a complex mixture
of products was observed without any traces of the desired
alkene. In order to circumvent this difficulty, an iron-catalyzed
cross-coupling between alkenyl Grignard reagents and alkyl
halides developed in our laboratory was successfully applied
to iodide 15 [FeCl3 (10 mol %), (E)-1-methyl-1-propenylmag-
nesium bromide (5 equiv), TMEDA (1.9 equiv), 0 °Ctort, THF]
(19) For a detailed study, see: Lorenz, M.; Bluhm, N.; Kalesse, M.
Synthesis 2009, 3061.
€
(20) (a) Arnarp, J.; Kenne, L.; Lindberg, B.; Lonngren, J. Carbohydr. Res.
1975, 44, C5–C7. For examples, see: (b) Walba, D. M.; Thurmes, W. N.;
Haltiwanger, R. C. J. Org. Chem. 1988, 53, 1046. (c) Paterson, I.; Ward,
R. A.; Smith, J. D.; Cumming, J. G.; Yeung, K.-S. Tetrahedron 1995, 51,
9437. (d) O’Neill, J. A.; Gallagher, O. P.; Devine, K. J.; Jones, P. W.;
Maguire, A. R. J. Nat. Prod. 2005, 68, 125.
(21) Difficulties were encountered for the transformation of 19 to its
corresponding methyl ether 20. Treatment of 19 with the Meerwein’s salt
successfully used in both Paterson et al. and Kalesse et al. syntheses led to
poor conversion of the substrate with 14 equiv of the reagent, whereas
degradation of 19 was observed in the presence of a larger excess (30 equiv).
Under our conditions [MeOTf (15 equiv), di-tert-butylpyridine (31 equiv),
50 °C, CH2Cl2] an excess of the reagents at 50 °C was required in order to
reach full conversion of 19, but a partial degradation was also observed thus
explaining the moderate 50% yield.
(14) (a) Wiskur, S. L.; Korte, A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126,
82. (b) For the hydrozirconation step, see: Hart, D. W.; Blackburn, T. F.;
Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679.
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SCHEME 8
HF Py was added by portions to ketone 20 in a THF/Py
advantage of the already prepared ketone 8 and alcohol 14
(Scheme 7).
3
mixture. Spiroketal 22 possessing two silyl ethers was isola-
ted and a NOESY experiment provided the assignment of the
relative stereochemistry of the substituents at C21 and C23.
However, we were unable to determine the position of the
two remaining silyl ethers in the spiroketal 22. Furthermore,
treatment of 22 with an excess of TBAF did not cleave the two
remaining silyl ethers. In order to perform the global deprotec-
As previously described in our first strategy, primary alcohol
14 was prepared from the (R)-Roche ester in nine steps with
an overall yield of 31% (Scheme 4). After protection of the
primary hydroxyl group as a PMB ether (PMBOC(dNH)-
CCl3, La(OTf)3, 0 °C to rt, toluene, 84%), the primary TBDPS
ether was selectively cleaved under treatment with TBAF/
AcOH (1/1) (68%). The oxidation of the resulting primary
alcohol 24 furnished aldehyde 25 (Dess-Martin perio-
dinane, rt, CH2Cl2) in 59% yield. At this stage, the aldol
coupling between aldehyde 25 and methyl ketone 8 was
considered, and the conditions described previously for the
condensation of 8 with 18 (LDA, -78 °C, THF) were selec-
ted. The aldol adducts 26 and 260 were produced with a
diastereomeric ratio of 3/1 in favor of the desired diastereo-
mer 26.18 Alcohols 26 and 260 were separated by flash
chromatography and 26 was isolated in 64% yield. It is
worth noting that the use of aldehyde 25 as the new coupling
partner considerably increased the yield of the aldolisation
(64% versus 45% in the first strategy) without affecting the
diastereoselectivity. Compound 26 was converted to its
corresponding methyl ether 27 using the Meerwein reagent
tion, 20 was treated with a large excess of HF Py, but once
3
again, the undesired reaction of the C30-C31 double bond was
observed (Scheme 6).22,23 In order to avoid this side reaction
which took place under the required acidic conditions for the
cleavage of the silyl ethers, a second strategy was designed.24
Second Strategy. In order to circumvent the difficulty
related to the presence of the electron-rich C30-C31 double
bond during the spiroketalization step, the iron-catalyzed
introduction of the olefinic moiety was planned after the
spiroketalization step. Spiroketal 1 would come from io-
dide H, which would be obtained from spiroketal I. The
latter would result from a deprotection/spiroketalization
sequence applied to ketone J, which should be formed thro-
ugh an aldol coupling between methyl ketone 8 and alde-
hyde K prepared from alcohol 14. This strategy is taking
(24) The protection of the C27 hydroxyl group as a PMB ether was first
envisioned in order to avoid the side reaction observed during the HF Py
mediated spiroketalization step. Unfortunately, the iron-catalyzed cross-
coupling of 34 with (E)-1-methyl-1-propenylmagnesium bromide failed in
the presence of the PMB ether group, and consequently, the synthesis of the
aldehyde partner for the aldol coupling could not be completed.
(22) Hypothetical structure for 33:
3
(23) This side reaction was not observed by Paterson et al.3,4 probably
because acetonide protecting groups are more labile than TBS ethers, thus
allowing the use of soft acidic conditions for their deprotection. Kalesse
et al.4 clearly mentioned that when TBS ethers were used instead of TES
ethers the deprotection/spiroketalisation step failed.
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SCHEME 9
˚
(Me3OBF4, proton sponge, MS 4 A, 0 °C to rt, CH2Cl2,
81%).25 Ketone 27 was then subjected to the deprotection/
spiroketalization step. Unfortunately, the acidic conditions
aqueous solution of NaHCO3 was added, and the two phases were
separated. The aqueous layer was extracted with CH2Cl2 (3 ꢀ
20 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (PE) to give 3 (889
mg, 89%): [R]20D = -9.1 (c 1.45, CHCl3); IR (neat) 2929, 2857,
1474, 1360, 1251, 1037, 1004 cm-1; 1H NMR (400 MHz, CDCl3) δ
5.90 (m, 1H), 5.05-4.97 (m, 2H), 3.76 (dd, J = 9.6, 4.6 Hz, 1H),
3.65-3.60 (m, 2H), 3.37 (dd, J = 10.0, 8.6 Hz, 1H), 2.30 (m, 1H),
1.86-1.72 (m, 2H), 1.01 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.0 Hz,
3H), 0.95-0.85 (m, 30H), 0.08-0.01 (m, 18H); 13C NMR (100
MHz, CDCl3) δ 140.8 (d), 114.8 (t), 76.8 (d), 76.5 (d), 65.2 (t),
43.8 (d), 42.7 (d), 39.1 (d), 26.3 (3q), 26.3 (3q), 26.1 (3q), 18.6 (s),
18.4 (s), 18.3 (s), 17.7 (q), 16.1 (q), 12.3 (q), -3.2 (q), -3.4 (q),
-3.5 (q), -4.3 (q), -5.5 (2q); MS (EI) 488 (1), 357 (12), 317 (32),
273 (16), 225 (48), 199 (100), 185 (15), 145 (20), 133 (13), 89 (63), 75
(25), 73 (97); HRMS (ESI) calcd for C29H64O3Si3 þ Liþ 551.4318,
found 551.4306.
required for the deprotection of the hydroxyl groups (HF Py)
3
also caused the cleavage of the PMB ether and a mixture of
products was obtained (Scheme 8).
Consequently, an acid-resistant protective group had to be
found for the C29 hydroxyl group, and we turned our choice
to a carbamate group. The primary PMB ether in 27 was
cleaved by using DDQ, and the resulting alcohol was treated
with phenylisocyanate to furnish carbamate 30 (53% for the
last two steps). The linear ketone 30 was then submitted to
HF Py, and pleasingly the desired spiroketal 31 was isolated
3
in a good yield of 81% (Scheme 9). An unequivocal determi-
nation of the C21/C23 stereochemistry was achieved by
NOESY analysis. This second strategy is promising and con-
stitutes an efficient way to access an highly functionalized
analogue of spiroketal 1 (Scheme 9).26
(3S,4S,5R,6S,7S)-3,5,7-Trimethyl-4,6,8-[tert-butyldimethyl-
silyloxy]-octan-1-ol (4). To a solution of alkene 3 (1.413 g, 2.60
mmol, 1 equiv) in THF (2 mL) at 0 °C was added dropwise
Conclusion
BH3 THF (1 M in THF, 2.86 mmol, 2.86 mL, 1.1 equiv). The
3
reaction mixture was stirred for 5 min at 0 °C and then allowed
to warm to rt. After 24 h, the reaction mixture was cooled to 0 °C,
and an aqueous sodium hydroxide solution (2.5 M, 5.71 mmol,
2.3 mL, 2.2 equiv) was added dropwise followed by the addition
of a hydrogen peroxide solution (35%, 23.58 mmol, 2.6 mL, 9.1
equiv). The resulting mixture was stirred at rt for 2 h and then
heated at reflux for 1 h. The two phases were separated, the
aqueous layer was extracted with Et2O (3 ꢀ 20 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated. A purification by flash chromatography on silica
gel (PE/Et2O 100/5 to 9/1) yielded the alcohol 4 (898 mg, 62%)
as a colorless oil: [R]20D=-10.7 (c 1.06, CHCl3); IR (neat) 3337,
2928, 2856, 1472, 1463, 1388, 1361, 1252, 1040, 1005 cm-1; 1H
NMR (400 MHz, CDCl3) δ 3.78-3.69 (m, 2H), 3.65-3.55 (m,
3H), 3.38 (dd, J = 9.9, 8.2 Hz, 1H), 1.91-1.81 (m, 2H), 1.80-
1.63 (m, 3H), 1.49 (m, 1H), 0.99-0.85 (m, 36H), 0.09-0.01 (m,
18H); 13C NMR (100 MHz, CDCl3) δ 77.5 (d) 76.7 (d), 65.3 (t),
Two convergent synthetic approaches of the spiroketal
core of spirangien A are described. Synthetic highlights
include a CBS reduction, an aldol coupling, and a deprotec-
tion/spiroketalization step that proceed with good dia-
stereoselectivities and excellent yields. In the first strategy,
the (E)-trisubstituted double bond was introduced via an
iron-catalyzed cross-coupling. In the second approach, we
were able to isolate a carbamate derivative featuring the
C13-C23 fragment of spirangien A incorporating 13 stereo-
genic centers.
Experimental Section
(3S,4S,5R,6S,7S)-3,5,7-Trimethyl-4,6,8-[tert-butyldimethylsilyl-
oxy]-oct-1-ene (3). To a solution of 28 (587 mg, 1.86 mmol, 1 equiv)
in CH2Cl2 (20 mL) at -78 °C were successively added 2,6-lutidine
(1.5 mL, 13.02 mmol, 7 equiv) and TBSOTf (1.5 mL, 6.50 mmol,
3.5 equiv). The reaction mixture was allowed to warm to rt slowly
without removing the bath and stirred overnight. Then, a saturated
(26) At this stage, we had to transform the carbamate group into an iodide
in order to install the C30-C31 double bond by mean of an iron-catalyzed
cross-coupling. In that goal, we first envisioned a protection of the four
alcohols as TES ethers, but unfortunately, a degradation of the substrate was
observed in presence of TESOTf, thus unabling us to complete the synthesis
of spiroketal 1.
(25) (a) Hans Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E.
J. Prakt. Chem. 1937, 147, 257. (b) Evans, D. A.; Ratz, A. M.; Huff, B. E.;
Sheppard, G. S. Tetrahedron Lett. 1994, 35, 7171. Also see refs 3 and 4.
J. Org. Chem. Vol. 75, No. 15, 2010 5157

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60.9 (t), 42.1 (d), 39.4 (d), 35.4 (d), 34.2 (t), 26.3 (3q), 26.1 (3q),
26.1 (3q), 18.7 (s), 18.4 (s), 18.4 (s), 17.1 (q), 15.7 (q), 12.4 (q),
-3.2 (q), -3.3 (q), -3.5 (q), -4.2 (q), -5.3 (2q); MS (EI) 357 (1),
75 (100), 73 (16), 56 (11); HRMS (ESI) calcd for C29H66O4Si3 þ
Liþ 569.4424, found 569.4410.
gylic alcohol 6 (520 mg, 86%) as a colorless oil. According to
GC/MS analysis of the crude product, the diastereoselectivity of
the reaction was 97/3. 6: [R]20D = -20.3 (c 0.95, CHCl3); IR
(neat) 3314, 2955, 2929, 2886, 2857, 1472, 1463, 1388, 1361,
1254, 1054 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.41 (m, 1H),
3.76 (dd, J = 10.0, 5.3 Hz, 1H), 3.65 (dd, J = 6.4, 2.7 Hz, 1H),
3.62 (dd, J = 4.9, 3.0 Hz, 1H), 3.38 (dd, J = 10.0, 8.4 Hz, 1H),
2.46 (d, J=2.0 Hz, 1H), 1.98-1.72 (m, 5H), 1.61-1.47 (m, 1H),
0.97 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 0.95-0.84 (m,
3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.89 (s, 9H), 0.10 (s, 6H), 0.08 (s,
6H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 85.8 (s), 77.0
(d), 76.7 (d), 72.7 (d), 65.5 (t), 60.5 (d), 42.0 (d), 39.9 (t), 39.6 (d),
35.0 (d), 26.4 (3q), 26.2 (3q), 26.2 (3q), 18.7 (s), 18.5 (s), 18.5 (s),
16.8 (q), 15.7 (q), 12.3 (q), -3.2 (q), -3.3 (q), -3.4 (q), -4.1 (q)
-5.2 (2q); MS (EI) 317 (1), 147 (19), 133 (11), 115 (15), 109 (20),
89 (46), 75 (49), 74 (11), 73 (100), 57 (12), 55 (12); HRMS (ESI)
calcd for C31H66O4Si3 þ Naþ 609.4161, found 609.4154.
(5S,6S,7R,8S,9S)-6,8,10-Tris(tert-butyldimethylsilyloxy)-5,7,9-
trimethyl-dec-1-yn-3-one (5). To a solution of alcohol 4 (1.36 g,
2.42 mmol, 1 equiv) in CH2Cl2 (50 mL) at 0 °C was added
Dess-Martin periodinane (1.54 g, 3.63 mmol, 1.5 equiv). The
reaction mixture was stirred for 15 min at 0 °C and then allowed
to warm to rt. After 2 h, a 10% aqueous solution of Na2S2O3 (25mL)
and a saturated aqueous solution of NaHCO3 (25 mL) were added.
After 30 min, the two phases were separated. The aqueous layer
was extracted with CH2Cl2 (3ꢀ50 mL), and the combined orga-
nic layers were dried over MgSO4, filtered, and concentrated.
The residue was filtered through a pad of silica gel to give the
desired aldehyde which was used in the following reaction with-
out any further purification.
(3S,5S,6S,7R,8S,9S)-3,6,8,10-Tetrakis(tert-butyldimethylsilyl-
oxy)-5,7,9-trimethyl-dec-1-yne (7). To a solution of alcohol 6
(508 mg, 0.87 mmol, 1 equiv) in CH2Cl2 (50 mL) at -78 °C were
added successively 2,6-lutidine (400 μL, 3.46 mmol, 4 equiv) and
TBSOTf (400 μL, 1.73 mmol, 2 equiv). After 2 h at -78 °C, the
reaction mixture was warmed to rt. After 20 h, a saturated
aqueous solution of NaHCO3 (50 mL) was added, and the two
phases were separated. The aqueous layer was extracted with
CH2Cl2 (3ꢀ50 mL), and the combined organic layers were dried
over MgSO4, filtered, and concentrated. The residue was puri-
fied by flash chromatography on silica gel (PE/EtOAc 100/0 to
The aldehyde (1.17 g, 2.09 mmol, 1 equiv) was dissolved in
THF (15 mL), and the resulting solution was cooled to 0 °C.
Ethynyl magnesium bromide (0.5 M in THF, 8.4 mL, 4.17 mmol,
2 equiv) was added dropwise. After 2 h at 0 °C, the reaction
mixture was quenched by addition of a saturated solution of
NH4Cl (10 mL). The two phases were separated, and the aque-
ous layer was extracted with EtOAc (3ꢀ10 mL). The combined
organic layers were dried over MgSO4, and the solvents were
removed in vacuo. The residue was purified by flash chromato-
graphy on silica gel (PE/EtOAc 100/3) and the alcohol was obta-
ined as a 1:1 mixture of diastereomers as a colorless oil (281 mg,
69% from 4). To a solution of the obtained alcohol (843 mg, 1.44
mmol, 1 equiv) in CH2Cl2 (30mL) at0°C was added Dess-Martin
periodinane (913 mg, 2.15 mmol, 1.5 equiv). After 15 min at 0 °C
and 2 h at rt, a 10% aqueous solution of Na2S2O3 (15 mL) and
saturated aqueous NaHCO3 (15 mL) were added. The mixture
was stirred for 30 min, and the two phases were separated. The
aqueous layer was extracted with CH2Cl2 (3 ꢀ 30 mL), and the
combined organic layers were dried over MgSO4, filtered, and
concentrated. A flash chromatography on silica gel (PE/EtOAc
100/2) afforded the propargylic ketone 5 as a colorless oil (787
mg, 61% for the three steps): [R]20D =þ2.5 (c 1.80, CHCl3); IR
(neat) 2956, 2930, 2886, 2858, 1686, 1472, 1463, 1388, 1361,
1255, 1071 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.73 (dd, J =
10.1, 5.7 Hz, 1H), 3.65 (dd, J=6.8, 3.0 Hz, 1H), 3.62 (dd, J=5.0,
2.91 Hz, 1H), 3.38 (dd, J=10.0, 8.0 Hz, 1H), 3.19 (s, 1H), 2.73
(dd, J=15.7, 2.7 Hz, 1H), 2.38 (dd, J=15.6, 10.4 Hz, 1H), 2.30
(m, 1H), 1.86 (m, 1H), 1.75 (qd, J=6.2, 1.5 Hz, 1H), 0.97-0.88
100/3) to give the alkyne 7as a colorless oil (590 mg, 97%): [R]20
=
D
-32.1 (c 1.30, CHCl3); IR (neat) 3313, 2956, 2929, 2886, 2858,
2367, 1472, 1463, 1389, 1361, 1254, 1086, 1039, 1005 cm-1; 1H
NMR (400 MHz, CDCl3) δ 4.39 (ddd, J=9.8, 3.4, 2.0 Hz, 1H),
3.78 (dd, J=10.0, 5.2 Hz, 1H), 3.69-3.58 (m, 2H), 3.34 (dd, J=
10.0, 8.6 Hz, 1H), 2.37 (d, J=2.1 Hz, 1H), 1.95-1.75 (m, 4H),
1.45 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.94-0.86 (m, 42H), 0.16
(s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.07
(s, 3H), 0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 86.5 (s),
77.4 (d), 77.2 (d), 72.0 (d), 65.5 (t), 60.6 (d), 41.9 (d), 40.2 (t), 39.3
(d), 34.7 (d), 26.4 (3q), 26.2 (3q), 26.2 (3q), 26.0 (3q), 18.7 (s),
18.5 (s), 18.5 (s), 18.3 (s), 15.9 (q), 15.8 (q), 12.4 (q), -3.3 (q),
-3.3 (q), -3.4 (q), -4.1 (q), -4.3 (q), -4.9 (q), -5.2 (q), -5.2
(q); HRMS (ESI) calcd for C37H80O4Si4 þ Naþ 723.5026, found
723.5027.
(3S,5S,6S,7R,8S,9S)-3,6,8,10-Tetrakis(tert-butyldimethylsilyl-
oxy)-5,7,9-trimethyl-decan-2-one (8). To a solution of 13 (60 mg,
0.086 mmol, 1 equiv) in THF (2 mL) were added successively
Hg(OAc)2 (5 mg, 0.019 mmol, 0.22 equiv), PPTS (11 mg, 0.120
mmol, 1.4 equiv), and water (20 μL). The reaction mixture was
heated at 45 °C and stirred at this temperature overnight. A
saturated aqueous solution of NaHCO3 (2 mL) and Et2O (2 mL)
were added. The two phases were separated, and the aqueous
layer was extracted with Et2O (3ꢀ5 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on
silica gel (PE/EtOAc 100/2), and the methyl ketone 8 (25 mg,
41%) was obtained: [R]20D = -30.3 (c 0.65, CHCl3); IR (neat)
(m, 36H), 0.09 (s, 3H), 0.08 (s, 6H), 0.07 (s, 3H), 0.03 (s, 6H); 13
C
NMR (100 MHz, CDCl3) δ 187.6 (s), 81.8 (d), 78.2 (s), 76.7 (d),
76.5 (d), 65.3 (t), 47.9 (t), 42.2 (d), 39.9 (d), 34.9 (d), 26.4 (3q),
26.2 (3q), 26.1 (3q), 18.7 (s), 18.5 (s), 18.4 (s), 17.6 (q), 15.3 (q),
12.5 (q), -3.0 (q), -3.4 (2q), -4.1 (q), -5.1 (2q); MS (EI) 395
(1), 239 (10), 147 (16), 115 (15), 89 (32), 75 (31), 73 (100), 57 (11);
HRMS (ESI) calcd for C31H64O4Si3 þ Naþ 607.4005, found
607.3991.
(3S,5S,6S,7R,8S,9S)-6,8,10-Tris(tert-butyldimethylsilyloxy)-
5,7,9-trimethyl-dec-1-yn-3-ol (6). To a solution of 5 (606 mg,
1.04 mmol, 1 equiv) in THF (12 mL) was added (S)-CBS (1 M in
toluene, 2.1 mL, 2.07 mmol, 2 equiv). The reaction mixture was
2929, 2857, 1718, 1462,1388, 1361, 1252, 1072, 1037, 1005 cm-1
;
1H NMR (400 MHz, CDCl3) δ 4.01 (dd, J=10.8, 2.3 Hz, 1H),
3.75 (dd, J = 10.1, 5.7 Hz, 1H), 3.65 (dd, J = 3.9, 3.9 Hz, 1H),
3.61 (dd, J = 7.2, 2.6 Hz, 1H), 3.35 (dd, J = 10.0, 7.8 Hz, 1H),
2.14 (s, 3H), 1.95-1.80 (m, 2H), 1.78-1.73 (m, 1H), 1.67 (ddd,
J = 13.3, 10.8, 2.1 Hz, 1H), 1.25 (m, 1H), 0.97-0.87 (m, 45H),
0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),
0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 212.5 (s), 77.4 (d),
77.2 (d), 77.0 (d), 65.3 (t), 41.5 (d), 39.7 (d), 36.4 (t), 34.5 (d), 26.3
(3q), 26.2 (3q), 26.2 (3q), 26.0 (3q), 24.7 (q), 18.7 (s), 18.5 (2s),
18.2 (s), 15.9 (q), 15.3 (q), 12.4 (q), -3.0 (q), -3.3 (q), -3.4 (q),
stirred for 15 min at rt, and then cooled to -30 °C. BH3 Me2S(2M
3
in THF, 2.6 mL, 5.18 mmol, 5 equiv) was added over 1.5 h via a
syringe pump. Once the addition was completed, the reaction
mixture was stirred for 1 h and ethanol (3.7 mL) was added
carefully. The mixture was warmed to rt and water and EtOAc
were added. The two phases were separated, and the aqueous
layer was extracted with EtOAc (3 ꢀ 20 mL). The combined
organic layers were dried over MgSO4, filtered and the solvent
was removed under reduced pressure. A flash chromatography
on silica gel (PE/EtOAc 100/1 to 100/3) furnished the propar-
5158 J. Org. Chem. Vol. 75, No. 15, 2010

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Guerinot et al.
JOCArticle
-3.9 (q), -4.6 (q), -4.9 (q), -5.2 (q), -5.2 (q); HRMS (ESI)
calcd for C37H82O5Si4 þ Naþ 741.5132, found 741.5131.
(3R,4R,5R)-3,5-Dimethyl-6-[tert-butyldiphenylsilyloxy]-hex-1-
en-4-ol (10). To a solution of (S,S)-Ti-I (11.5 mmol, 1.15 equiv)
at -78 °C in Et2O (100 mL) was added a solution of (R)-3-(tert-
butyldiphethylsilyloxy)-2-methyl-propionaldehyde 913 (3.26 g,
10 mmol, 1 equiv) in Et2O (15 mL). After 20 h at -78 °C,
deionized water (50 mL) was added. After 24 h at rt, the reaction
media was filtered on a pad of Celite, the two phases were
separated, and the aqueous layer was extracted with EtOAc (3ꢀ
100 mL). The organic layer was washed with a saturated aque-
ous solution of NaCl, dried over MgSO4, and filtered, and the
solvent was removed under reduced pressure. Pentane (150 mL)
was added and after 3 h of vigorous stirring at rt, (S,S)-Taddol
was filtered off. The filtrate was concentrated and the crude was
purified by flash chromatography on silica gel (PE/Et2O 100/5,
95/5 then 9/1) to give the homoallylic alcohol 10 (2.707 g, 71%)
as a colorless oil. The diastereomeric ratio was estimated to be
95/5 by 1H NMR analysis. 10: [R]20D=-4.4 (c 1.09, CHCl3); IR
(neat) 3504, 2930, 2857, 1638, 1471, 1427, 1389, 1107 cm-1; 1H
NMR (400 MHz, CDCl3) δ7.71-7.65 (m, 4H), 7.46-7.35 (m, 6H),
5.88-5.77 (ddd, J=16.6, 10.5, 8.5 Hz, 1H), 5.15-5.05 (m, 2H),
3.72 (d, J = 5.0 Hz, 2H), 3.59 (dtapp, J = 8.5, 2.9 Hz, 1H), 2.42
(d, J = 2.5 Hz, 1H), 2.28 (m, 1H), 1.82 (m, 1H), 1.06 (s, 9H), 0.94
(d, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 142.0 (d),
135.8 (2d), 135.7 (2d), 133.5 (s), 133.4 (s), 129.8 (2d), 127.8 (4d),
115.5 (t), 76.2 (d), 68.5 (t), 41.8 (d), 36.7 (d), 27.0 (3q), 19.3 (s),
16.8 (q), 9.7 (q); MS (EI) 325 ([M - t-Bu]þ, 2), 269 (13), 200 (19),
199 (100), 197 (11), 183 (16), 181 (12), 135 (17), 109 (71), 67 (11);
HRMS (ESI) calcd for C24H34O2Si þ Naþ 405.2226, found
405.2225.
(0.079 M in tert-butanol, 1.9 mL, 0.15 mmol, 0.02 equiv) and
NMO (964 mg, 8.24 mmol, 1.1 equiv) were added. After 20 h at
rt, solid Na2S2O3 (8 g), Celite (16 g), and EtOAc (30 mL) were
added. The mixture was filtered through a pad of Celite which
was thoroughly washed with EtOAc. The filtrate was evapo-
rated under reduced pressure, and the residue was dissolved in a
1/1 mixture of water and THF (80 mL). Sodium periodate (4.00 g,
18.69 mmol, 2.5 equiv) was added to this solution and after 3 h,
the mixture was filtered through a pad of Celite. The two phases
were separated, and the aqueous layer was extracted with
EtOAc (3 ꢀ 100 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo to give the
aldehyde which was used without further purification in the
following step. To a solution of (R,R)-Ti-II (10.49 mmol, 1.4
equiv) at -78 °C in Et2O (70 mL) was added a solution of the
previous aldehyde (7.49 mmol, 1 equiv) in Et2O (15 mL). After
20 h at -78 °C, deionized water (100 mL) was added, and the
mixture was allowed to warm to rt. After 72 h at rt, the reaction
mixture was filtered through a pad of Celite, the two phases were
separated, and the aqueous layer was extracted with EtOAc (3ꢀ
100 mL). The organic layer was washed with a saturated aqueous
solution of NaCl, dried over MgSO4, and filtered, and the sol-
vent was removed under reduced pressure. Pentane (100 mL)
was added, and after 20 h of vigorous stirring at rt, the precipi-
tated (R,R)-Taddol was filtered off. The filtrate was concentra-
ted, and the crude was purified by flash chromatography on silica
gel (PE/Et2O 100/3 to 100/5) to give homoallylic alcohol 12
(3.317 g, 80%, 3 steps) as a colorless oil. The diastereomeric ratio
was estimated to 98/2 by 1H NMR analysis. 12: [R]20D =-20.9
(c 1.12, CHCl3); IR (neat) 3497, 2957, 2929, 2856, 1638, 1589,
1471, 1461, 1387, 1360, 1252, 1105, 1044, 1001 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.67-7.61 (m, 4H), 7.45-7.34 (m, 6H),
5.79 (m, 1H), 5.12-5.03 (m, 2H), 3.92 (t, J = 3.5 Hz, 1H), 3.61-
3.55 (m, 2H), 3.48 (dd, J = 9.9, 6.5 Hz, 1H), 2.90 (d, J = 1.7 Hz,
1H), 2.22 (sextapp, J=7.8 Hz, 1H), 1.95 (m, 1H), 1.71 (m, 1H),
1.05 (s, 9H), 0.95 (d, J = 7.1 Hz, 3H), 0.93 (d, J = 7.4 Hz, 3H),
0.88 (s, 9H), 0.79 (d, J = 7.1 Hz, 3H), 0.09 (s, 3H), 0.02 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 142.5 (d), 135.7 (4d), 133.8 (2s),
129.7 (2d), 127.7 (4d), 114.9 (t), 77.6 (d), 74.3 (d), 66.9 (t), 41.7
(d), 39.4 (d), 37.4 (d), 27.0 (3q), 26.3 (3q), 19.3 (s), 18.5 (s), 16.5
(q), 12.9 (q), 11.1 (q), -3.6 (q), -3.9 (q); MS (EI) 365 (3), 281
(10), 239 (15), 199 (44), 197 (17), 195 (10), 183 (16), 149 (12), 91
(12), 78 (25), 75 (100), 73 (18), 56 (13), 55 (13); HRMS (ESI)
calcd for C33H54O3Si2 þ Naþ: 577.3504, found 577.3504.
(3S,4S,5R,6S,7R)-3,5,7-Trimethyl-4,6-[tert-butyldimethylsilyl-
oxy]-8-[tert-butyldiphenylsilyloxy]-oct-1-ene (13). To a solution
of alcohol 12 (3.317 g, 5.98 mmol, 1 equiv) in CH2Cl2 (60 mL) at
-78 °C were added successively 2,6-lutidine (2.1 mL, 17.94
mmol, 3 equiv) and TBSOTf (2.1 mL, 8.97 mmol, 1.5 equiv).
The reaction mixture was allowed to slowly warm to rt. After 20 h,
the mixture was cooled to -78 °C and treated with additional por-
tions of 2,6-lutidine (0.7 mL, 5.98 mmol, 1 equiv) and TBSOTf
(0.7 mL, 2.99 mmol, 0.5 equiv). A saturated aqueous solution of
NaHCO3 (50 mL) was added, the two phases were separated,
and the aqueous layer was extracted with CH2Cl2 (3ꢀ150 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated. The crude product was purified by flash
chromatography on silica gel (PE/Et2O 100/5) to afford alkene
13 (5.35 g, 90%) as a colorless oil: [R]20D=-7.0 (c 1.01, CHCl3);
(3R,4R,5R)-3,5-Dimethyl-4-[tert-butyldimethylsilyloxy]-6-[tert-
butyldiphenylsilyloxy]-hex-1-ene (11). To a solution of alcohol 10
(4.63 g, 12.08 mmol, 1 equiv) in CH2Cl2 (120 mL) at -78 °C were
added successively 2,6-lutidine (4.1 mL, 36.23 mmol, 3 equiv) and
TBSOTf (4.1 mL, 18.11 mmol, 1.5 equiv). The reaction mixture
was allowed to slowly warm to rt and stirred overnight. A satu-
rated aqueous solution of NaHCO3 (100 mL) was added, the two
phases were separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 150 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel (PE/Et2O: 100/5)
to afford alkene 11 (5.35 g, 90%) as a colorless oil: [R]20D=-1.7
(c0.95, CHCl3); IR (neat) 2929, 2856, 1639, 1589, 1461, 1360, 1251,
1110, 1048, 1004 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.62
(m, 4H), 7.44-7.33 (m, 6H), 5.80 (m, 1H), 4.96-4.88 (m, 2H),
3.75 (dd, J = 3.5, 4.8 Hz, 1H), 3.54 (dd, J = 10.1 Hz, 7.2 Hz, 1H),
3.42 (dd, J = 9.1, 6.4 Hz, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 1.05 (s,
9H), 0.97 (d, J = 7.2 Hz, 3H), 0.87 (s, 9H), 0.84 (d, J = 6.9 Hz,
3H), 0.03 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
142.0 (d), 135.7 (2d), 135.7 (2d), 134.1 (s), 134.1 (s), 129.6 (2d),
127.6 (4d), 114.1 (t), 75.3 (d), 66.9 (t), 43.2 (d), 39.1 (d), 27.0 (3q),
26.2 (3q), 19.4 (s), 18.5 (s), 17.1 (q), 12.0 (q), -3.6 (q), -4.0 (q);
MS (EI) 443 (2), 439 ([M - t-Bu]þ,15), 383 (11), 382 (28), 381 (79),
313 (21), 307 (25), 293 (13), 272 (12), 271 (44), 269 (12), 257 (12),
253 (13), 251 (17), 235 (20), 227 (14), 211 (19), 210 (16), 209 (74),
200 (13), 199 (74), 198 (13), 197 (64), 195 (42), 193 (29), 191 (16),
189 (18), 181 (26), 179 (11), 175 (15), 165 (17), 163 (16), 145 (31),
136 (14), 135 (100), 121 (10), 115 (12), 109 (56), 105 (19), 91 (39),
75 (35), 73 (53), 67 (10), 59 (12); HRMS (ESI) calcd for C30H48-
O2Si2 þ Naþ 519.3085, found 519.3084.
1
IR (neat) 2928, 1471, 1360, 1251, 1110, 1040, 1004 cm-1; H
NMR (400 MHz, CDCl3) δ 7.69-7.61 (m, 4H), 7.45-7.33 (m,
6H), 5.85 (m, 1H), 5.07-4.99 (m, 2H), 3.90 (d, J = 6.0 Hz, 1H),
3.55 (dd, J=6.0, 2.5 Hz, 1H), 3.46 (dd, J=9.6, 9.6 Hz, 1H), 3.33
(dd, J = 9.5 Hz, 6.1 Hz, 1H), 2.39 (m, 1H), 1.88-1.76 (m, 2H),
1.06 (s, 9H), 0.98 (d, J = 7.1 Hz, 3H), 0.92 (s, 9H), 0.89 (d, J =
7.0 Hz, 3H), 0.84 (s, 9H), 0.78 (d, J = 6.5 Hz, 3H), 0.08 (s, 6H),
0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.5
(d), 135.7 (2d), 135.7 (2d), 134.0 (s), 134.0 (s), 129.6 (2d), 127.7
(3S,4S,5R,6S,7R)-3,5,7-Trimethyl-6-[tert-butyldimethylsilyl-
oxy]-8-[tert-butyldiphenylsilyloxy]-oct-1-en-4-ol (12). To a solu-
tion of alkene 11 (3.753 g, 7.49 mmol, 1 equiv) in a mixture of
water and tert-butanol (1/1, 40 mL) were added osmium
tetroxide (0.079 M in tert-butanol, 1.9 mL, 0.15 mmol, 0.02 equiv)
and NMO (964 mg, 8.24 mmol, 1.1 equiv). The reaction mixture
was stirred for 8 h, and additional portions of osmium tetroxide
J. Org. Chem. Vol. 75, No. 15, 2010 5159

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JOCArticle
(4d), 114.9 (t), 76.7 (d), 71.7 (d), 67.6 (t), 43.4 (d), 42.4 (d), 37.6
(d), 27.0 (3q), 26.3 (3q), 26.1 (3q), 19.3 (s), 18.6 (s), 18.4 (s), 17.1
(q), 12.3 (q), 11.3 (q), -3.3 (q), -3.3 (q), -3.4 (q), -4.6 (q); MS
(EI) 482 (3), 349 (10), 293 (10), 253 (13), 251 (16), 239 (26), 227
(20), 209 (17), 207 (10), 200 (17), 199 (100), 195 (19), 193 (10), 191
(12), 185 (10), 183 (22), 149 (15), 147 (11), 145 (22), 135 (65), 133
(12), 115 (21), 91 (39), 75 (55), 73 (83); HRMS (ESI) calcd for
C39H68O3Si3 þ Naþ 691.4369, found 691.4375.
(neat) 2928, 2856, 1471, 1427, 1388, 1360, 1522, 1106, 1042, 1005
cm-1 1H NMR (400 MHz, CDCl3) δ 7.68-7.62 (m, 4H),
;
7.44-7.34 (m, 6H), 3.81 (dd, J = 6.4, 0.9 Hz, 1H), 3.66 (tapp
,
J=4.0 Hz, 1H), 3.49 (dd, J = 9.5, 8.0 Hz, 1H), 3.38 (dd, J = 10.1,
6.5 Hz, 1H), 3.35 (dd, J = 9.6, 4.0 Hz, 1H), 2.95 (tapp, J = 9.6 Hz,
1H), 1.93 (m, 1H), 1.88-1.74 (m, 2H), 1.07 (s, 9H), 1.03 (d, J = 6.9
Hz, 3H), 0.90 (s, 9H), 0.88 (d, J= 7.6 Hz, 3H), 0.84 (s, 9H), 0.81 (d,
J = 6.6 Hz, 3H), 0.09 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), -0.04 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 135.7 (4d), 133.9 (2s), 129.6
(2d), 127.7 (4d), 75.8 (d), 73.1 (d), 67.5 (t), 42.5 (d), 42.3 (d), 38.1
(d), 27.1 (3q), 26.2 (3q), 26.1 (3q), 19.3 (s), 18.6 (s), 18.5 (s), 18.0 (q),
12.1 (q), 11.1 (q), 11.1 (t), -3.0 (q), -3.0 (q), -3.1 (q), -3.4 (q);
MS (EI) 511 (1), 313 (21), 309 (14), 199 (18), 197 (12), 185 (11), 157
(14), 135 (23), 115 (29), 91 (12), 78 (30), 77 (17), 75 (100), 67 (10), 57
(20), 56 (21), 55 (11); HRMS (ESI) calcd for C38H67O3ISi3 þ Naþ
805.3335, found 805.3339.
(2S,3S,4R,5S,6R)-2,4,6-Trimethyl-3,5-[tert-butyldimethylsilyl-
oxy]-7-[tert-butyldiphenylsilyloxy]-heptan-1-ol (14). To a solu-
tion of alkene 13 (2.589 g, 3.88 mmol, 1 equiv) in a 1/1 mixture of
water and tert-butanol (20 mL) were added osmium tetroxide
(0.079 M in tert-butanol, 1.5 mL, 0.12 mmol, 0.03 equiv) and
NMO (500 mg, 4.26 mmol, 1.1 equiv). The reaction mixture was
stirred for 8 h, and additional portions of osmium tetroxide
(0.079 M in tert-butanol, 1.5 mL, 0.12 mmol, 0.03 equiv) and
NMO (500 mg, 4.26 mmol, 1.1 equiv) were added. After 20 h at
rt, solid Na2S2O3 (8 g), Celite (16 g) and EtOAc (30 mL) were
added. The mixture was filtered through a pad of Celite which
was thoroughly washed with EtOAc. The filtrate was evapo-
rated under reduced pressure, and the residue was dissolved in a
1/1 mixture of water/THF (80 mL). Sodium periodate (4.00 g,
18.69 mmol, 4.9 equiv) was added to this solution. After 5 h, the
mixture was filtered through a pad of Celite. The two phases
were separated, and the aqueous layer was extracted with
EtOAc (3 ꢀ 100 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo to give the
aldehyde which was used without any further purification in the
following step. To a solution of the previous synthesized alde-
hyde (3.88 mmol, 1 equiv) in methanol (40 mL) at 0 °C was
added portionwise NaBH4 (442 mg, 11.63 mmol, 3 equiv). The
reaction mixture was warmed to rt and after 1 h, a saturated
aqueous solution of NH4Cl (40 mL), a saturated aqueous solu-
tion of potassium/sodium tartrate (40 mL) and EtOAc (120 mL)
were added. After 1 h, the two phases were separated. The aque-
ous layer was extracted with EtOAc (3ꢀ100 mL), and the combined
organic layers were dried over MgSO4, filtered, and concentra-
ted under reduced pressure. The residue was purified by flash
chromatography on silica gel (PE/Et2O 9/1) to afford the pri-
(E)-1-Methyl-1-propenylmagnesium Bromide. (E)-2-bromo-
but-2-ene (510 μL, 5 mmol, 1 equiv) was dissolved in Et2O (3 mL),
and the solution was cooled to -78 °C. t-BuLi (1.7 M pentane,
6 mL, 10 mmol, 2 equiv) was added dropwise, and the mixture
was stirred for 2 h at -78 °C and then 45 min at 0 °C. After
cooling to -78 °C, the mixture was added dropwise to a suspen-
sion of MgBr2 OEt2 (1.455 g, 5.680 mmol, 1.1 equiv) in THF (4 mL)
3
at -78 °C. Once the addition was complete, the mixture was
allowed to warm to rt and stirred for 2 h. Pentane and Et2O were
removed carefully under reduced pressure. THF (6 mL) was
added to the mixture in order to obtain a ca. 0.5 M solution of
the Grignard reagent.
(E)-(5S,6S,7R,8S,9R)-6,8-Bis(tert-butyldimethylsilyloxy)-10-
(tert-butyldiphenylsilyloxy)-3,5,7,9-tetramethyl-dec-2-ene (16).
To a solution of primary alkyl iodide 15 (312 mg, 0.40 mmol,
1 equiv) and anhydrous FeCl3 (0.1 M in THF, 400 μL, 0.04 mmol,
0.1 equiv) at 0 °C in THF (1 mL) was added a premixed solution
of TMEDA (380 μL, 0.76 mmol, 1.9 equiv) and (E)-1-methyl-
1-propenylmagnesium bromide (0.5 M in THF, 4 mL, 2.00 mmol,
5 equiv) via a syringe pump at a 5 mL/h rate. Once the addition
was completed, the reaction mixture was warmed to rt. After
30 min, the mixture was quenched by addition of a saturated
aqueous solution of NH4Cl (1 mL). The two phases were sepa-
rated, and the aqueous layer was extracted with diethyl ether (3ꢀ
5 mL). The organic layers were combined, dried over MgSO4,
filtered, and concentrated. The same reaction was repeated on
alkyl iodide 22 (344 mg, 0.440 mmol, 1 equiv). The two crude
products were combined for purification, which was achieved by
flash chromatography on silica gel (PE/EtOAc 100/1 to 100/5)
mary alcohol 14 (2.07 g, 79%, 3 steps) as a colorless oil: [R]20
=
D
-9.8 (c 1.05, CHCl3); IR (neat) 3440, 2928, 2856, 1471, 1360,
1
1251, 1108, 1043, 1004 cm-1; H NMR (400 MHz, CDCl3) δ
7.67-7.58 (m, 4H), 7.45-7.33 (m, 6H), 3.96 (dapp, J = 6.0 Hz,
1H), 3.92 (dd, J = 10.9, 4.1 Hz, 1H), 3.69 (dd, J = 6.7, 2.3 Hz,
1H), 3.53 (dd, J = 10.9, 4.1 Hz, 1H), 3.47 (tapp, J = 9.4 Hz, 1H),
3.35 (dd, J = 9.0, 6.0 Hz, 1H), 2.59 (m, 1H, OH), 1.98 (sextapp
,
to give the alkene 16 (451 mg, 76%) as a colorless oil: [R]20
=
D
J=7.0 Hz, 1H), 1.84 (m, 1H), 1.75 (m, 1H), 1.05 (s, 9H), 1.02 (d,
J=7.1 Hz, 3H), 0.96 (d, J = 7.1 Hz, 3H), 0.92 (s, 9H), 0.85 (s,
9H), 0.78 (d, J= 7.1 Hz, 3H), 0.14 (s, 3H), 0.11 (s, 3H), 0.09 (s,
3H), 0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.6 (2d),
135.5 (2d), 133.9 (s), 133.8 (s), 129.7 (2d), 127.7 (4d), 79.1 (d),
71.6 (d), 67.1 (t), 65.1 (t), 43.1 (d), 38.2 (d), 37.7 (d), 27.0 (3q),
26.3 (3q), 26.1 (3q), 19.2 (s), 18.5 (s), 18.5 (s), 15.8 (q), 13.0 (q),
11.0 (q), -3.1 (q), -3.3 (2q), -4.4 (q); MS (EI) 483 (3), 227 (12),
207 (13), 199 (19), 197 (20), 185 (25), 145 (17), 115 (10), 91 (12),
78 (45), 77 (18), 75 (100), 73 (31), 56 (18); HRMS (ESI) calcd for
C38H68O4Si3 þ Naþ 695.4318, found 695.4314.
-1.33 (c 0.75, CHCl3); IR (neat) 2956, 2929, 2857, 1472, 1428,
1388, 1361, 1252, 1112, 1044, 1006 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.69-7.61 (m, 4H), 7.44-7.33 (m, 6H), 5.17 (q, J=5.7
Hz, 1H), 3.77 (dapp, J=5.8 Hz, 1H), 3.57-3.54 (m, 1H), 3.47 (m,
1H), 3.36 (dd, J = 12.5, 9.7 Hz, 1H), 2.09 (d, J = 9.7 Hz, 1H),
1.92 (m, 1H), 1.85 (m, 1H), 1.78-1.71 (m, 2H), 1.56-1.54 (2s,
6H), 1.06 (s, 9H), 0.94-0.89 (m, 12H), 0.86-0.82 (m, 12H), 0.78
(d, J=6.4 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), -0.06
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 135.8 (2d), 135.8 (2d),
134.4 (s), 134.1 (s), 134.0 (s), 129.7 (2d), 127.7 (4d), 120.1 (d),
76.8 (d), 73.4 (d), 67.9 (t), 42.4 (t), 41.7 (d), 37.8 (d), 37.4 (d), 27.1
(3q), 26.4 (3q), 26.2 (3q), 19.4 (s), 18.7 (s), 18.5 (s), 15.8 (q), 15.5
(q), 13.6 (q), 11.9 (q), 11.4 (q), -3.2 (q), -3.3 (q), -3.5 (q), -4.4
(q); HRMS (ESI) calcd for C42H74O3Si3 þ Naþ 733.4838, found
733.4842.
(E)-(2R,3S,4R,5S,6S)-3,5-Bis(tert-butyldimethylsilyloxy)-2,4,6,8-
tetramethyl-dec-8-en-1-ol (17). To a solution of alkene 16 (585 mg,
0.82 mmol, 1 equiv) in THF (10 mL) was added an equimolar
mixture of AcOH/TBAF portionwise over 2 days (7 additions of
1.7 mL, ca. 11.9 mL added over two days, 11.54 mmol, 14 equiv). A
saturated aqueous solution of NaHCO3 was then added (20 mL),
and the two phases were separated. The aqueous layer was extracted
(2S,3S,4S,5R,6R)-1-Iodo-2,4,6-trimethyl-3,5-[tert-butyldimethyl-
silyloxy]-7-[tert-butyldiphenylsilyloxy]-heptane (15). To a solution
of 14 (1.06 g, 1.58 mmol, 1 equiv) in CH2Cl2 (20 mL) were added
successively triphenylphosphine (870 mg, 3.31 mmol, 2.1 equiv)
and imidazole (343 mg, 5.05 mmol, 2.1 equiv). After complete
dissolution, the mixture was cooled to 0 °C, and iodine (841 mg,
3.31 mmol, 2.1 equiv) was added. After 30 min at 0 °C, the mixture
was warmed to rt and stirred overnight. The solvent was removed
in vacuo, and the crude was purified by flash chromatography on
silica gel (PE/Et2O 100/2 to 100/4) to afford primary alkyl iodide 15
(1.197 g, 97%) as a colorless oil: [R]20D=-4.2 (c 1.28, CHCl3); IR
5160 J. Org. Chem. Vol. 75, No. 15, 2010

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Guerinot et al.
JOCArticle
with Et2O (3ꢀ30 mL), and the combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (PE/
EtOAc 100/2), and the primary alcohol 17 was obtained (284 mg,
73%) as a colorless oil: [R]20D =-19.9 (c 1.15, CHCl3); IR (neat)
were separated, and the aqueous layer was extracted with CH2Cl2
(3ꢀ1 mL). The combined organic layers were washed with a satu-
rated aqueous solution of NH4Cl (3 mL), dried over MgSO4,
and concentrated in vacuo. A flash chromatography on silica gel
(PE/toluene 95/5 to 8/2) afforded 20 (21 mg, 50%): [R]20
=
D
1
2929, 2857, 1472, 1386, 1361, 1253, 1037, 1006 cm-1; H NMR
-12.4 (c 0.25, CHCl3); IR (neat): 2932, 2858, 2362, 1721, 1472,
1361, 1255, 1091, 1037, 1006 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.20 (m, 1H), 4.09 (dapp, J=10.0 Hz, 1H), 3.85 (d, J=5.0 Hz,
1H), 3.74 (dd, J=10.3, 5.7 Hz, 1H), 3.67-3.56 (m, 3H), 3.51 (br
d, J=4.8 Hz, 1H), 3.35 (tapp, J=9.3 Hz, 1H), 3.23 (s, 3H), 2.71
(dd, J=17.4, 7.9 Hz, 1H), 2.48 (dd, J=17.7, 2.6 Hz, 1H), 2.07
(m, 1H), 1.93-1.72 (m, 8H), 1.59 (s, 3H), 1.55 (s, 3H), 1.34 (m,
1H), 0.95 (d, J=6.8 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H), 0.93-0.87
(m, 3H), 0.92 (s, 9H), 0.91 (s, 18H), 0.89 (s, 9H), 0.89 (s, 9H), 0.87
(s, 9H), 0.86 (d, J=7.4 Hz, 3H), 0.79 (d, J=6.4 Hz, 3H), 0.78 (d,
J=6.8 Hz, 3H), 0.09 (s, 3H), 0.09 (s, 3H), 0.08-0.05 (m, 18H),
0.04 (s, 3H), 0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 212.3
(s), 134.4 (s), 120.1 (d), 79.8 (d), 77.5 (d), 77.3 (d), 76.9 (d), 76.8
(d), 73.1 (d), 65.3 (t), 57.8 (q), 42.4 (d), 41.7 (t), 41.7 (d), 40.6 (d),
39.8 (t), 38.1 (d), 36.3 (d), 35.6 (t), 34.7 (d), 26.4 (6q), 26.2 (6q),
26.1 (3q), 26.1 (3q), 18.7 (s), 18.7 (s), 18.5 (2s), 18.4 (s), 18.3 (s),
16.3 (q), 16.0 (q), 15.7 (q), 15.2 (q), 13.5 (q), 12.5 (q), 11.7 (q), 11.0
(q), -2.9 (q), -3.2 (q), -3.2 (q), -3.3 (q), -3.4 (q), -3.5 (q), -3.9
(q), -4.2 (q), -4.4 (q), -4.9 (q), -5.2 (q), -5.2 (q); HRMS (ESI)
calcd for C64H138O8Si6 þ Naþ 1225.8900, found 1225.8904.
Spiroketal 22. To a solution of 20 (40 mg, 0.033 mmol, 1 equiv)
(400 MHz, CDCl3) δ 5.24-5.15 (m, 1H), 3.79 (dd, J=6.3, 1.3 Hz,
1H), 3.53 (dd, J=4.3, 3.1 Hz, 1H), 3.51-3.41 (m, 2H), 2.11 (dapp
,
J= 9.5 Hz, 1H), 1.92-1.71 (m, 4H), 1.57 (2 br s, 6H), 1.39 (br s,
1H, OH), 0.94-0.90 (m, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.89 (d, J=
7.0 Hz, 3H), 0.79 (d, J=6.4 Hz, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07
(2s, 6H); 13C NMR (100 MHz, CDCl3) δ 134.4 (s), 120.2 (d), 77.1
(d), 73.7 (d), 67.2 (t), 42.2 (t), 41.5 (d), 37.8 (d), 36.6 (d), 26.3 (3q),
26.2 (3q), 18.7 (s), 18.5 (s), 15.9 (q), 15.7 (q), 13.5 (q), 12.0 (q), 11.6
(q), -3.1 (q), -3.2 (q), -3.4 (q), -4.4 (q); HRMS (ESI) calcd for
C26H56O3Si2 þ Naþ 495.3660, found 495.3653.
(E)-(2S,3S,4R,5S,6S,8S,11R,12R,13S,14R,15S,16S)-1,3,5,8,
13,15-Hexakis(tert-butyldimethylsilyloxy)-11-hydroxy-2,4,6,12,14,
16,18-heptamethyl-icos-18-en-9-one (19). To a solution of alco-
hol 17 (176 mg, 0.37 mmol, 1 equiv) in CH2Cl2 (30 mL) at 0 °C was
added Dess-Martin periodinane (395 mg, 0.93 mmol, 2.5 equiv).
The reaction mixture was stirred for 15 min at 0 °C and then
warmed to rt. After 2 h at rt, a saturated aqueous solution of
Na2S2O3 (15 mL) and a saturated aqueous solution of NaHCO3
(15 mL) were added, and the mixture was stirred for 45 min. The
two phases were separated, the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 30 mL), and the combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was filtered on silica gel (PE/EtOAc 100/3)
to afford aldehyde 18 (174 mg, 99%). To a solution of methyl
ketone 8 (302 mg, 0.420 mmol, 1 equiv) at -78 °C in THF (2 mL)
was added a freshly prepared solution of LDA (0.5 M in THF,
1.09 mL, 0.55 mmol, 1.3 equiv). The reaction mixture was stirred
for 2 h at -78 °C and a solution of aldehyde 18 (99 mg, 0.21
mmol, 0.5 equiv) in THF (1 mL) was added. After 2 h at -78 °C
a saturated aqueous solution of NH4Cl (3 mL) was added, and
the mixture was warmed to rt. The two phases were separated,
and the aqueous layer was extracted with EtOAc (3 ꢀ 30 mL).
The combined organic layers were dried over MgSO4, filtered,
in THF/Py (1.2 mL/10 μL) was added portionwise HF Py (200 μL,
3
7.920 mmol, 240 equiv) over 16 h. NaHCO3 solid was added until
pH 6-7, the suspension was filtered, and the filtrate was evapo-
rated under reduced pressure. The residue was purified by flash
chromatography (CH2Cl2/MeOH 100/0 to 100/3) to give 22 (6 mg,
25%) contaminated with an unknown impurity: [R]20D = -5.8
(c 0.6, CHCl3); IR (neat): 3384, 2957, 2929, 2857, 1716, 1462, 1386,
1361, 1253, 1033, 1005 cm-1 1H NMR (600 MHz, C6D6) δ
;
5.60-5.53 (m, 1H), 4.25 (m, 1H), 4.07-3.99 (m, 1H), 3.99-3.93
(m, 2H), 3.87-3.78 (m, 2H), 3.72-3.66 (m, 1H), 3.52-3.46 (m,
1H), 3.40 (s, 3H), 2.61-2.51 (m, 1H), 2.40-2.12 (m, 7H), 2.06-
1.91 (m, 2H), 1.91-1.84 (m, 4H), 1.77-1.70 (m, 3H), 1.70-1.60
(m, 1H), 1.55-0.89 (m, 30H), 0.57-0.49 (m, 6H), 0.49-0.22 (m,
12H); 13C NMR (100 MHz, C6D6) δ 135.0 (s), 121.0 (d), 97.8 (s),
80.8 (d), 80.5 (d), 78.3 (d), 77.3 (d), 73.7 (d), 70.0 (d), 64.0 (t), 55.4
(q), 44.6 (d), 42.7 (t), 41.9 (t), 38.0 (d), 37.2 (d), 36.7 (t), 35.7 (d),
35.1 (d), 27.9 (d), 26.3 (3q), 26.2 (3q), 21.9 (q), 18.7 (s), 18.5 (s), 17.7
(q), 16.4 (q), 16.4 (q), 14.1 (q), 13.8 (q), 12.4 (q), 10.2 (q), -3.1 (q),
-3.3 (q), -3.4 (q), -4.5 (q); HRMS (ESI) calcd for C40H80O7Si2 þ
Naþ 751.5335, found 751.5352.
1
and concentrated in vacuo. A H NMR analysis of the crude
product allowed to estimate the diastereomeric ratio 19/190 to be
3/1. The crude product was purified by flash chromatography
(PE/toluene 85/15 to 5/5) to afford the ketone 19 (112 mg, 45%),
its diastereomer 190 as a mixture with aldehyde 18 (25 mg), and
the recovered methyl ketone 8 (150 mg). Compound 19: [R]20
=
D
-10.0 (c 1.65, CHCl3); IR (neat) 2956, 2929, 2886, 2858, 2366,
1707, 1472, 1463, 1388, 1361, 1254, 1077, 1034, 1006 cm-1; 1H
NMR (400 MHz, CDCl3) δ 5.20 (m, 1H), 4.18 (d, J = 6.2 Hz,
1H), 4.02 (d, J = 11.0 Hz, 1H), 3.81-3.70 (m, 2H), 3.70-3.60
(m, 3H), 3.40-3.27 (m, 2H), 3.01 (d, J=18.4 Hz, 1H), 2.34 (dd,
J=18.7, 10.0 Hz, 1H), 2.13 (d, J=12.5 Hz, 1H), 1.95-1.62 (m,
9H), 1.57 (br s, 6H), 0.98-0.85 (m, 66H), 0.78 (d, J = 7.0 Hz,
6H), 0.13-0.01 (m, 36H); 13C NMR (100 MHz, CDCl3) δ 216.7
(s), 134.6 (s), 120.0 (d), 77.4 (d), 77.3 (d), 77.3 (d), 77.0 (d), 76.8
(d), 72.0 (d), 69.0 (d), 65.3 (t), 42.1 (t), 41.6 (d), 41.5 (d), 41.2 (t),
39.9 (d), 39.6 (d), 36.6 (d), 36.3 (t), 26.4 (6q), 26.3 (3q), 26.2 (3q),
26.2 (3q), 26.0 (3q), 18.7 (s), 18.7 (s), 18.6 (s), 18.5 (2s), 18.2 (s),
16.1 (q), 15.8 (q), 15.6 (q), 15.3 (q), 13.5 (q), 12.5 (q), 12.0 (q),
11.0 (q), -3.0 (q), -3.1 (q), -3.2 (q), -3.3 (2q), -3.4 (q), -3.9 (q),
-4.3 (q), -4.6 (q), -4.9 (q), -5.2 (q), -5.2 (q); HRMS (ESI)
calcd for C63H136O8Si6 þ Naþ 1211.8743, found 1211.8740.
(E)-(2S,3S,4R,5S,6S,8S,11R,12R,13S,14R,15S,16S)-1,3,5,8,
13,15-Hexakis(tert-butyldimethylsilyloxy)-11-methoxy-2,4,6,12,
14,16,18-heptamethyl-icos-18-en-9-one (20). To a solution of 19
(42 mg, 0.035 mmol, 1 equiv) in CH2Cl2 (400 μL) were added di-
tert-butylpyridine (142 μL, 1.08 mmol, 31 equiv) and methyl
triflate (107 μL, 0.533 mmol, 15 equiv). After 24 h at 50 °C, the
reaction mixture was poured into water (1 mL), the two phases
1-Methoxy-4-[(2S,3S,4R,5S,6R)-3,5-bis(tert-butyldimethyl-
silyloxy)-7-(tert-butyldiphenylsilyloxy)-2,4,6-trimethylheptyloxy-
methyl]benzene (23). To a solution of 14 (1.21 g, 1.78 mmol, 1
equiv) in toluene (12 mL) were added at 0 °C PMBOC(dNH)-
CCl3 (1.00 g, 3.56 mmol, 2 equiv) and La(OTf)3 (52 mg, 0.09
mmol, 0.05 equiv). After 2 h at rt, the reaction mixture was
filtered through a pad of Celite (Et2O), and the resulting filtrate
was evaporated under vacuum. The residue was purified by flash
chromatography on silica gel (PE/Et2O 100/0 to 100/3) to give
23 (1.19 g, 84%): [R]20D=-0.30 (c 3.0, CHCl3); IR (neat) 3072,
2956, 2930, 2886, 2858, 1613, 1588, 1513, 1472, 1462, 1428, 1389,
1361, 1302, 1249, 1172, 1111, 1085, 1040, 1006 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.70-7.65 (m, 4H), 7.45-7.34 (m, 6H),
7.26-7.22 (m, 2H), 6.87-6.84 (m, 2H), 4.44 (d, J = 11.6 Hz,
1H), 4.40 (d, J=11.6 Hz, 1H), 3.85 (d, J=7.0 Hz, 1H), 3.79 (s,
3H), 3.68 (tapp, J=4.0 Hz, 1H), 3.58-3.49 (m, 2H), 3.38 (dd, J=
10.1, 7.0 Hz, 1H), 3.22 (dd, J = 9.0, 7.8 Hz, 1H), 2.05 (m, 1H),
1.94-1.85 (m, 2H), 1.08 (s, 9H), 0.96 (d, J=6.9 Hz, 3H), 0.91 (s,
9H), 0.90 (m, 3H), 0.85 (s, 9H), 0.84 (d, J=6.8 Hz, 3H), 0.10 (s,
3H), 0.09 (s, 3H), 0.03 (s, 3H), -0.06 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.1 (s), 135.7 (2d), 135.7 (2d), 134.1 (s), 134.0
(s), 131.0 (s), 129.6 (d), 129.6 (d), 129.2 (2d), 127.7 (4d), 113.8
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(2d), 75.3 (d), 73.0 (d), 72.8 (t), 72.2 (t), 67.7 (t), 55.3 (q), 42.2 (d),
39.5 (d), 37.9 (d), 27.1 (3q), 26.3 (3q), 26.1 (3q), 19.3 (s), 18.7 (s),
18.5 (s), 15.0 (q), 12.1 (q), 11.1 (q), -3.3 (2q), -3.4 (q), -4.5 (q);
HRMS (ESI) calcd for C46H76O5Si3 þ Naþ 815.4893, found
815.4905.
(d, J=6.9 Hz, 3H), 0.94-0.91 (m, 6H), 0.92 (s, 9H), 0.90 (s, 9H),
0.89 (2s, 18H), 0.88 (s, 9H), 0.87 (s, 9H), 0.83 (d, J=7.0 Hz, 3H),
0.76 (d, J=7.0 Hz, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (2s, 6H),
0.07 (2s, 6H), 0.06 (2s, 6H), 0.04 (3s, 9H), 0.01 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 216.5 (s), 159.1 (s), 131.0 (s), 129.2 (2d),
113.8 (2d), 77.4 (d), 77.2 (d), 76.9 (d), 74.7 (d), 72.8 (t), 72.5 (t),
72.3 (d), 68.7 (d), 65.3 (t), 55.3 (q), 41.8 (d), 41.6 (d), 41.2 (t), 40.1
(d), 39.6 (2d), 36.2 (t), 34.4 (d), 26.3 (3q), 26.3 (3q), 26.3 (3q),
26.3 (3q), 26.2 (3q), 25.9 (3q), 18.7 (s), 18.6 (s), 18.6 (s), 18.4 (2s),
18.1 (s), 16.1 (q), 15.2 (q), 15.0 (q), 12.4 (q), 11.7 (q), 10.5 (q),
-3.0 (q), -3.1 (q), -3.1 (q), -3.3 (q), -3.4 (q), -3.5 (q), -3.9 (q),
-4.1 (q), -4.6 (q), -5.0 (q), -5.2 (q), -5.3 (q); HRMS (ESI)
calcd for C67H138O10Si6 þ Naþ 1293.8799, found 1293.8805.
(2S,3S,4R,5S,6R,7R,10S,12S,13S,14R,15S,16S)-3,5,10,13,15,
17-Hexakis(tert-butyldimethylsilyloxy)-7-methoxy-1-(4-methoxy-
benzyloxy)-2,4,6,12,14,16-hexamethylheptadecan-9-one (27). To
a solution of alcohol 26 (128 mg, 0.10 mmol, 1 equiv) in CH2Cl2
(2R,3S,4S,5S,6S)-3,5-Bis(tert-butyldimethylsilyloxy)-7-(4-meth-
oxybenzyloxy)-2,4,6-trimethylheptan-1-ol (24). To a solution of
23 (1.19 g, 1.49 mmol, 1 equiv) in THF (20 mL) was added
an equimolar mixture of AcOH/TBAF portionwise over 2 days
(6 additions of 1.0 mL, a total of ca. 6.0 mL added over 2 days,
17.88 mmol, 12 equiv). A saturated aqueous solution of
NaHCO3 was then added (20 mL), and the two phases were
separated. The aqueous layer was extracted with Et2O (3 ꢀ 30
mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (PE/Et2O 100/0 to 9/1), and
the primary alcohol 24 was obtained (644 mg, 68%) as a colorless
oil: [R]20D =-13.6 (c 0.85, CHCl3); IR (neat) 3435, 2956, 2930,
2885, 2857, 1613, 1587, 1514, 1463, 1387, 1361, 1302, 1250, 1173,
1085, 1037, 1006 cm-1;1HNMR(400 MHz, CDCl3) δ7.25 (d, J=
8.0 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 4.42 (m, 2H), 3.80 (s, 3H),
3.78 (dd, J = 6.3, 1.3 Hz, 1H), 3.68 (tapp, J = 4.2 Hz, 1H),
3.56-3.40 (m, 3H), 3.24 (dd, J=7.9, 0.6 Hz, 1H), 1.98 (m, 1H),
1.91-1.77 (m, 2H), 1.59 (m, 1H, OH), 0.95 (d, J=6.8 Hz, 3H),
0.90-0.86 (m, 6H), 0.89 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s,
3H), 0.05 (2s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.1 (s),
130.8 (s), 129.2 (2d), 113.8 (2d), 74.8 (d), 73.7 (d), 72.8 (t), 72.3
(t), 66.9 (t), 55.4 (q), 41.7 (d), 39.3 (d), 38.0 (d), 26.2 (3q), 26.1
(3q), 18.6 (s), 18.5 (s), 14.7 (q), 11.8 (q), 11.3 (q), -3.3 (2q), -3.5
(q), -4.4 (q); HRMS (ESI) calcd for C30H58O5Si2 þ Naþ
577.3715, found 577.3706.
˚
(1.8 mL) at 0 °C were added MS 4 A (55 mg), proton sponge (134
mg, 0.61 mmol, 6 equiv), and Me3OBF4 (77 mg, 0.50 mmol,
5 equiv). The reaction mixture was warmed to rt and after 2 h,
additional portions of proton sponge (134 mg, 0.605 mmol, 6 equiv)
and Me3OBF4 (77 mg, 0.502 mmol, 5 equiv) were added. After 2 h,
a saturated aqueous solution of NaHCO3 (1 mL) was added. The
two phases were separated, and the aqueous phase was extracted
with CH2Cl2 (3ꢀ2 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel (PE/EtOAc
100/1 to 100/3) to give 27 (104 mg, 81%): [R]20D =-9.8 (c 1.05,
CHCl3); IR (neat) 2956, 2930, 2857, 1727, 1614, 1514, 1463,
1388, 1361, 1252, 1087, 1038, 1005 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.25 (d, J=8.6 Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 4.45
(d, J=11.5 Hz, 1H), 4.39 (d, J=11.8 Hz, 1H), 4.09 (dd, J=10.6,
2.0 Hz, 1H), 3.83 (d, J=5.0 Hz, 1H), 3.80 (s, 3H), 3.74 (dd, J=
9.9, 5.4 Hz, 1H), 3.67-3.58 (m, 4H), 3.54 (dd, J = 9.1, 5.4 Hz,
1H), 3.34 (dd, J = 9.8, 8.4 Hz, 1H), 3.23 (m, 1H), 3.21 (s, 3H),
2.71 (dd, J=17.3, 8.1 Hz, 1H), 2.46 (dd, J=17.4, 3.0 Hz, 1H),
2.03 (m, 1H), 1.94-1.63 (m, 6H), 1.35 (m, 1H), 0.98-0.93 (m,
9H), 0.92 (s, 9H), 0.98 (3s, 27H), 0.90-0.86 (m, 6H), 0.88 (2s,
18H), 0.76 (d, J=7.0 Hz, 3H), 0.07 (s, 6H), 0.07 (s, 3H), 0.06 (s,
6H), 0.06 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s,
6H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 212.1 (s), 159.1
(s), 130.9 (s), 129.2 (2d), 113.8 (2d), 79.5 (d), 77.5 (d), 77.3 (d),
76.9 (d), 75.1 (d), 73.2 (d), 72.9 (t), 72.2 (t), 65.3 (t), 57.6 (q), 55.3
(q), 42.9 (d), 41.7 (d), 40.3 (t), 39.7 (d), 39.1 (d), 38.2 (d), 35.5 (t),
34.6 (d), 26.3 (3q), 26.3 (3q), 26.2 (3q), 26.2 (3q), 26.1 (3q), 26.0
(3q), 18.6 (2s), 18.5 (s), 18.4 (s), 18.4 (s), 18.2 (s), 16.3 (q), 15.1
(q), 15.1 (q), 12.4 (q), 11.7 (q), 10.8 (q), -3.0 (q), -3.4 (3q), -3.5
(q), -3.5 (q), -4.0 (q), -4.2 (q), -4.5 (q), -5.0 (q), -5.2 (q), -5.3
(q); HRMS (ESI) calcd for C68H140O10Si6 þ Naþ 1307.8954,
found 1307.8955.
(2S,3S,4R,5S,6R,7R,10S,12S,13S,14R,15S,16S)-3,5,10,13,15,
17-Hexakis(tert-butyldimethylsilyloxy)-7-hydroxy-1-(4-methoxy-
benzyloxy)-2,4,6,12,14,16-hexamethylheptadecan-9-one (26). To
a solution of alcohol 24 (300 mg, 0.48 mmol, 1 equiv) in CH2Cl2
(40 mL) at 0 °C was added Dess-Martin periodinane (402 mg,
0.95 mmol, 2 equiv). After 15 min at 0 °C and 2 h at rt, saturated
aqueous solutions of Na2S2O3 (20 mL) and NaHCO3 (20 mL)
were added, and the mixture was stirred for 45 min. The two
phases were separated, the aqueous layer was extracted with
CH2Cl2 (3ꢀ30 mL), and the combined organic layers were dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was filtered on silica gel (PE/Et2O 100/5) to afford
aldehyde 25 (178 mg, 59%). To a solution of methyl ketone
8 (320 mg, 0.45 mmol, 1 equiv) at -78 °C in THF (2 mL) was
added LDA (0.5 M in THF, 1.2 mL, 0.58 mmol, 1.3 equiv). The
reaction mixture was stirred for 2 h at -78 °C, and a solution of
the previously prepared aldehyde 25 (140 mg, 0.22 mmol, 0.5
equiv) in THF (1 mL) was added. After 2 h at -78 °C, a satu-
rated aqueous solution of NH4Cl (3 mL) was added, the mixture
was warmed to rt, the two phases were separated, and the aque-
ous layer was extracted with EtOAc (3 ꢀ 3 mL). The combined
organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. The diastereomeric ratio 26/260 was estimated to
(2S,3S,4R,5S,6R,7R,10S,12S,13S,14R,15S,16S)-3,5,10,13,15,
17-Hexakis(tert-butyldimethylsilyloxy)-1-hydroxy-7-methoxy-2,4,
6,12,14,16-hexamethyl-heptadecan-9-one (29). To a solution of
27 (80 mg, 0.062 mmol, 1 equiv) in a 5/1 mixture of CH2Cl2 /
buffer pH=7 (1 mL/0.2 mL) at 0 °C was added DDQ (17 mg,
0.075 mmol, 1.2 equiv). The reaction mixture was warmed to rt
over 1 h. After 30 min, a saturated aqueous solution of
NaHCO3 (1 mL) and Et2O (2 mL) were added. After 30 min,
water (2 mL) was added, and the two phases were separated.
The aqueous phase was extracted with Et2O (3ꢀ4 mL), and the
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (PE/EtOAc 100/2 to 100/4) to
1
3/1 by H NMR analysis. The crude product was purified by
flash chromatography (PE/toluene 8/2 to 5/5 and then PE/
EtOAc 100/2 to 100/4) to afford ketone 26 (192 mg, 64%), a mix-
ture of diastereomer 260 and aldehyde 25 (74 mg) and the re-
covered methyl ketone 8 (118 mg). Compound 26: [R]20D =-11.8
(c 0.65, CHCl3); IR (neat) 3552, 3527, 2954, 2928, 2885, 2856,
1705, 1613, 1513, 1471, 1462, 1387, 1360, 1302, 1250, 1216, 1171,
1076, 1032, 1005 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.26 (m,
2H), 6.66 (m, 2H), 4.44 (d, J=11.6 Hz, 1H), 4.39 (d, J=11.6 Hz,
1H), 4.17 (d, J = 7.4 Hz, 1H), 4.02 (dd, J = 10.7, 1.9 Hz, 1H),
3.80 (s, 3H), 3.78-3.71 (m, 3H), 3.66-3.55 (m, 3H), 3.35 (dd,
J = 9.9, 8.0 Hz, 1H), 3.24 (tapp, J = 8.7 Hz, 1H), 3.01 (dd, J =
18.7, 1.9 Hz, 1H), 2.35 (dd, J=18.2, 9.4 Hz, 1H), 2.02 (m, 1H),
1.95-1.53 (m, 6H), 1.25 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.96
give the primary alcohol 29 (47 mg, 64%): [R]20 = -12.6
D
(c 2.35, CHCl3); IR (neat) 2956, 2930, 2886, 2858, 1719, 1472,
1388, 1361, 1254, 1083, 1035, 1005 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.09 (dd, J=10.7, 2.0 Hz, 1H), 3.87 (dd, J=4.8, 1.5
Hz, 1H), 3.83 (m, 1H), 3.74 (dd, J = 10.0, 5.8 Hz, 1H),
5162 J. Org. Chem. Vol. 75, No. 15, 2010

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3.70-3.55 (m, 5H), 3.35 (dd, J=9.9, 8.4 Hz, 1H), 3.24 (s, 3H),
2.72 (dd, J=17.6, 7.5 Hz, 1H), 2.54 (m, 1H, OH), 2.50 (dd, J=
17.8, 3.2 Hz, 1H), 2.63-1.62 (m, 7H), 1.38-1.23 (m, 1H), 1.05
(d, J = 7.2 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.95 (d,
J = 7.0 Hz, 3H), 0.93-0.85 (m, 6H), 0.93 (s, 9H), 0.92 (s,
9H), 0.91 (s, 9H), 0.89 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.78 (d,
J=7.0 Hz, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.10 (s,
3H), 0.08 (2s, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03
(s, 3H), 0.03 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 212.0 (s), 79.2 (d), 77.6 (d), 77.5 (d), 77.3 (d), 77.0 (d), 72.4 (d),
65.3 (t), 65.1 (t), 57.6 (q), 44.0 (d), 41.7 (d), 40.2 (t), 39.7 (d),
39.1 (d), 38.5 (d), 35.7 (t), 34.6 (d), 26.3 (6q), 26.2 (3q), 26.2
(3q), 26.1 (3q), 26.0 (3q), 18.6 (s), 18.5 (s), 18.5 (s), 18.4 (s), 18.4
(s), 18.2 (s), 16.2 (q), 15.3 (q), 15.1 (q), 12.4 (q), 12.1 (q), 11.0
(q), -3.0 (q), -3.4 (2q), -3.4 (2q), -3.5 (q), -3.9 (q), -4.1 (q),
-4.5 (q), -4.9 (q), -5.2 (q), -5.3 (q); HRMS (ESI) calcd for
(s), 18.2 (s), 16.2 (q), 15.0 (q), 13.9 (q), 12.4 (q), 11.4 (q), 10.6 (q),
-3.0 (q), -3.2 (q), -3.4 (q), -3.4 (q), -3.6 (q), -3.7 (q), -3.9
(q), -4.1 (q), -4.5 (q), -4.9 (q), -5.2 (q), -5.3 (q); HRMS
(ESI) calcd for C67H137NO10Si6 þ Naþ 1306.8789, found
1306.8750.
Phenyl Carbamic Acid (2S,3R,4S)-4-[(2R,3S,4R,6R,7S,9S)-
10-((1R,2R,3S)-2,4-dihydroxy-1,3-dimethylbutyl)-7-hydroxy-4-
methoxy-3,9-dimethylspiro[5.5]undec-2-yl]-3-hydroxy-2-methyl-
pentyl Ester (31). To a solution of 30 (43 mg, 0.034 mmol,
1 equiv) in THF (2 mL) at 0 °C was added HF Py (1.5 mL, 61.20
3
mmol, 1800 equiv). The reaction mixture was stirred for 5 min at
0 °C and then allowed to warm to rt. After 2 h, solid NaHCO3
was added carefully until pH 5-6. The resulting suspension was
filtered, and the filtrate was evaporated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH 100/1 to 100/5) to give spiroketal 31 (16 mg,
81%): [R]20D=þ0.4 (c 0.8, CHCl3); IR (neat) 3393, 2971, 2929,
1710, 1602, 1544, 1502, 1445, 1383, 1314, 1228, 1180, 1153, 1083,
1056, 1028 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.37 (d, J=7.3
Hz, 2H), 7.30 (t, J=7.6 Hz, 2H), 7.07 (t, J=7.3 Hz, 1H), 6.70 (br
s, 1H), 4.47 (dd, J=10.8, 4.8 Hz, 1H), 4.24 (dd, J=10.8, 3.8 Hz,
1H), 3.89 (dd, J = 8.9, 8.9 Hz, 1H), 3.87 (d, J = 11.1 Hz, 1H),
3.77 (d, J=10.2 Hz, 1H), 3.67 (dd, J=11.1, 4.5 Hz, 1H), 3.58 (d,
J = 10.2 Hz, 1H), 3.56-3.50 (m, 2H), 3.46 (br s, 1H), 3.35 (s,
3H), 2.15 (quint, J=6.6 Hz, 1H), 2.04 (dd, J=13.4, 4.8 Hz, 1H),
1.98 (td, J=7.2, 3.5 Hz, 1H), 1.95-1.90 (m, 1H), 1.90-1.78 (m,
3H), 1.74 (t, J=13.4 Hz, 1H), 1.65 (ddd, J=13.0, 3.3, 3.0 Hz,
1H), 1.41 (t, J=12.6 Hz, 1H), 1.09 (d, J=7.0 Hz, 3H), 0.97 (d,
J = 6.7 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz,
3H), 0.79 (d, J=6.7 Hz, 3H), 0.74 (d, J=6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 154.7 (s), 138.3 (s), 129.5 (2d), 124.0 (d),
119.3 (2d), 98.8 (s), 79.4 (d), 77.4 (d), 74.3 (d), 72.2 (d), 71.1 (d),
70.8 (d), 69.2 (t), 66.8 (t), 55.8 (q), 37.6 (d), 37.2 (d), 36.4 (d), 35.8
(d), 35.7 (t), 33.1 (t), 32.3 (d), 24.9 (d), 17.9 (q), 16.0 (q), 14.6 (q),
10.5 (q), 8.0 (q), 4.4 (q). HRMS (ESI) calcd for C31H51O9N þ
Naþ 604.3456, found 604.3445.
C
60H132O9Si6 þ Naþ 1187.8379, found 1187.8408.
Phenyl Carbamic Acid (2S,3S,4R,5S,6R,7R,10S,12S,13S,14R,
15S,16S)-3,5,10,13,15,17-hexakis(tert-butyldimethylsilyloxy)-
7-methoxy-2,4,6,12,14,16-hexamethyl-9-oxo-heptadecyl Ester (30).
Alcohol 29 (47 mg, 0.040 mmol, 1 equiv) was dissolved in pyri-
dine (400 μL) and phenylisocyanate (44 μL, 0.400 mmol, 10 equiv)
was added. After 4 h at rt, a 10% solution of CuSO4 in water was
added (1 mL), the two phases were separated, and the aqueous
layer was extracted with Et2O (3ꢀ2 mL). The combined organic
phases were washed with a solution of CuSO4 (10 wt % in H2O,
3 ꢀ 5 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. A flash chromatography on silica gel (PE/
EtOAc 100/1 to 100/2) afforded carbamate 30 (43 mg, 83%):
[R]20D=-9.2 (c 2.15, CHCl3); IR (neat) 2956, 2930, 2858, 1721,
1602, 1536, 1501, 1472, 1444, 1388, 1361, 1312, 1253, 1215, 1081,
1005 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.1 Hz,
2H), 7.30 (t, J=7.8 Hz, 2H), 7.03 (m, 1H, NH), 7.05 (t, J=7.3
Hz, 1H), 4.20-4.09 (m, 3H), 3.86 (dd, J=4.6, 1.3 Hz, 1H), 3.75
(dd, J=10.0, 5.8 Hz, 1H), 3.72-3.65 (m, 3H), 3.63 (dd, J=7.6,
2.5 Hz, 1H), 3.36 (dd, J=9.9, 8.4 Hz, 1H), 3.24 (s, 3H), 2.75 (dd,
J=17.5, 8.6 Hz, 1H), 2.45 (dd, J=17.7, 2.8 Hz, 1H), 2.19-2.11
(m, 1H), 1.99-1.66 (m, 6H), 1.38-1.25 (m, 1H), 0.99 (d, J=7.0
Hz, 3H), 0.96 (d, J=6.8 Hz, 6H), 0.93 (s, 9H), 0.92 (s, 9H), 0.91
(s, 9H), 0.89 (2s, 18H), 0.88 (s, 9H), 0.93-0.88 (m, 6H), 0.80
(d, J=6.9 Hz, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.08 (s,
3H), 0.08 (3s, 9H), 0.06 (s, 3H), 0.04 (4s, 12H); 13C NMR
(100 MHz, CDCl3) δ 212.5 (s), 153.7 (s), 138.3 (s), 129.1 (2d),
123.3 (d), 118.8 (2d), 79.8 (d), 77.6 (d), 77.3 (d), 77.0 (d), 73.9 (d),
72.9 (d), 67.1 (t), 65.3 (t), 57.5 (q), 42.6 (d), 41.6 (d), 39.9 (t), 39.8
(d), 38.6 (d), 37.8 (d), 35.7 (t), 34.7 (d), 26.3 (3q), 26.2 (3q), 26.2
(6q), 26.1 (3q), 26.0 (3q), 18.6 (s), 18.6 (s), 18.5 (s), 18.4 (s), 18.4
Acknowledgment. The CNRS (grant to A.G.) is gratefully
acknowledged.
Supporting Information Available: 1H and 13C NMR spec-
tra for compounds 3-8, 10-17, 19, 20, 22-24, 26-27, and 29-
31, NMR assignment for diastereoisomers 19/190 and 26/260,
measurable coupling constants and NOE diagnostics for the
spiroketal core of 31. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5163